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Alzheimer's disease (AD) genetics implies a causal role for innate immune genes, TREM2 and CD33, products that oppose each other in the downstream Syk tyrosine kinase pathway, activating microglial phagocytosis of amyloid (Aβ). We report effects of low (Curc-lo) and high (Curc-hi) doses of curcumin on neuroinflammation in APPsw transgenic mice. Results showed that Curc-lo decreased CD33 and increased TREM2 expression (predicted to decrease AD risk) and also increased TyroBP, which controls a neuroinflammatory gene network implicated in AD as well as phagocytosis markers CD68 and Arg1. Curc-lo coordinately restored tightly correlated relationships between these genes' expression levels, and decreased expression of genes characteristic of toxic pro-inflammatory M1 microglia (CD11b, iNOS, COX-2, IL1β). In contrast, very high dose curcumin did not show these effects, failed to clear amyloid plaques, and dysregulated gene expression relationships. Curc-lo stimulated microglial migration to and phagocytosis of amyloid plaques both in vivo and in ex vivo assays of sections of human AD brain and of mouse brain. Curcumin also reduced levels of miR-155, a micro-RNA reported to drive a neurodegenerative microglial phenotype. In conditions without amyloid (human microglial cells in vitro, aged wild-type mice), Curc-lo similarly decreased CD33 and increased TREM2. Like curcumin, anti-Aβ antibody (also reported to engage the Syk pathway, increase CD68, and decrease amyloid burden in human and mouse brain) increased TREM2 in APPsw mice and decreased amyloid in human AD sections ex vivo. We conclude that curcumin is an immunomodulatory treatment capable of emulating anti-Aβ vaccine in stimulating phagocytic clearance of amyloid by reducing CD33 and increasing TREM2 and TyroBP, while restoring neuroinflammatory networks implicated in neurodegenerative diseases.

Curcumin, a polyphenolic antioxidant derived from the turmeric root has undergone extensive preclinical development, showing remarkable efficacy in wound repair, cancer and inflammatory disorders. This review addresses the rationale for its use in neurodegenerative disease, particularly Alzheimer’s disease (AD). Curcumin is a pleiotropic molecule, which not only directly binds to and limits aggregation of the β-sheet conformations of amyloid characteristic of many neurodegenerative diseases but also restores homeostasis of the inflammatory system, boosts the heat shock system to enhance clearance of toxic aggregates, scavenges free radicals, chelates iron and induces anti-oxidant response elements. Although curcumin corrects dysregulation of multiple pathways, it may exert many effects via a few molecular targets. Pharmaceutical development of natural compounds like curcumin and synthetic derivatives have strong scientific rationale, but will require overcoming various hurdles including; high cost of trials, concern about profitability and misconceptions about drug specificity, stability and bioavailability.

The Apolipoprotein E (ApoE) isotype ApoE4 is a prevalent genetic risk factor for Alzheimer's disease (AD) that can modulate systemic and central inflammation, independent of amyloid accumulation. Although disruption of innate immune toll receptor signaling is modulated by ApoE and observed in AD, ApoE isotype-specific effects remain poorly understood. Therefore, we examined the effect of the ApoE isotype on the brain levels of major regulators of TLR signaling including miR146a, a microRNA enriched in the brain. We used 6-month-old ApoE3 or ApoE4 targeted replacement mice with and without mutant familial AD transgenes. ApoE4 reduced the levels of miR146a compared with ApoE3, both in the brain (29%; P

Aging contributes to physiological decline and vulnerability to disease. In the brain, even with minimal neuronal loss, aging increases oxidative damage, inflammation, demyelination, impaired processing, and metabolic deficits, particularly during pathological brain aging. In this review, the possible role of docosahexaenoic acid (DHA) in the prevention of age-related disruption of brain function is discussed. High-fat diabetogenic diets, cholesterol, and the omega-6 fatty acid arachidonate and its prostaglandin metabolites have all been implicated in promoting the pathogenesis of Alzheimer's disease. Evidence presented here shows DHA acts to oppose this, exerting a plethora of pleiotropic activities to protect against the pathogenesis of Alzheimer's disease.

Alzheimer's disease (AD) is accompanied by an activation of the innate immune system, and many epidemiological studies have shown reduced risk for dementia or AD associated with chronic consumption of non-steroidal anti-inflammatory drugs (NSAIDs). These observations led to animal model studies to test the hypothesis that NSAIDs can be disease-modifying for some aspects of AD pathogenesis. NSAIDs cannot only suppress inflammatory targets, which could contribute to neuroprotection, they also slow amyloid deposition by mechanisms that remain unclear. Several large clinical trials with NSAID therapies with AD subjects have failed, and cyclooxygenase-2 does not appear to be a useful target for disease modifying therapy. However, there may be apolipoprotein E E4 pharmacogenomic effects and a real but delayed positive signal in a large primary prevention trial with naproxen. This encourages researchers to re-address possible mechanisms for a stage-dependent NSAID efficacy, the subject of this review.

The onset of age-related neurodegenerative diseases superimposed on a declining nervous system could enhance the motor and cognitive behavioral deficits that normally occur in senescence. It is likely that, in cases of severe deficits in memory or motor function, hospitalization and/or custodial care would be a likely outcome. This means that unless some way is found to reduce these age-related decrements in neuronal function, health care costs will continue to rise exponentially. Applying molecular biological approaches to slow aging in the human condition may be years away. So, it is important to determine what methods can be used today to increase healthy aging, forestall the onset of these diseases, and create conditions favorable to obtaining a “longevity dividend” in both financial and human terms. Recent studies suggest that consumption of diets rich in antioxidants and anti-inflammatory components such as those found in fruits, nuts, vegetables, and spices, or even reduced caloric intake, may lower age-related cognitive declines and the risk of developing neurodegenerative disease.

More than a dozen epidemiological studies have reported that reduced levels or intake of omega-3 fatty acids or fish consumption is associated with increased risk for age-related cognitive decline or dementia such as Alzheimer's disease (AD). Increased dietary consumption or blood levels of docosahexaenoic acid (DHA) appear protective for AD and other dementia in multiple epidemiological studies; however, three studies suggest that the ApoE4 genotype limits protection. DHA is broadly neuroprotective via multiple mechanisms that include neuroprotective DHA metabolites, reduced arachidonic acid metabolites, and increased trophic factors or downstream trophic signal transduction. DHA is also protective against several risk factors for dementia including head trauma, diabetes, and cardiovascular disease. DHA is specifically protective against AD via additional mechanisms: It limits the production and accumulation of the amyloid beta peptide toxin that is widely believed to drive the disease; and it also suppresses several signal transduction pathways induced by Abeta, including two major kinases that phosphorylate the microtubule-associated protein tau and promote neurofibrillary tangle pathology. Based on the epidemiological and basic research data, expert panels have recommended the need for clinical trials with omega-3 fatty acids, notably DHA, for the prevention or treatment of age-related cognitive decline--with a focus on the most prevalent cause, AD. Clinical trials are underway to prevent and treat AD. Results to-date suggest that DHA may be more effective if it is begun early or used in conjunction with antioxidants.

Both insulin resistance (type II diabetes) and beta-amyloid (Abeta) oligomers are implicated in Alzheimer's disease (AD). Here, we investigate the role of Abeta oligomer-induced c-Jun N-terminal kinase (JNK) activation leading to phosphorylation and degradation of the adaptor protein insulin receptor substrate-1 (IRS-1). IRS-1 couples insulin and other trophic factor receptors to downstream kinases and neuroprotective signaling. Increased phospho-IRS-1 is found in AD brain and insulin-resistant tissues from diabetics. Here, we report Abeta oligomers significantly increased active JNK and phosphorylation of IRS-1 (Ser616) and tau (Ser422) in cultured hippocampal neurons, whereas JNK inhibition blocked these responses. The omega-3 fatty acid docosahexaenoic acid (DHA) similarly inhibited JNK and the phosphorylation of IRS-1 and tau in cultured hippocampal neurons. Feeding 3xTg-AD transgenic mice a diet high in saturated and omega-6 fat increased active JNK and phosphorylated IRS-1 and tau. Treatment of the 3xTg-AD mice on high-fat diet with fish oil or curcumin or a combination of both for 4 months reduced phosphorylated JNK, IRS-1, and tau and prevented the degradation of total IRS-1. This was accompanied by improvement in Y-maze performance. Mice fed with fish oil and curcumin for 1 month had more significant effects on Y-maze, and the combination showed more significant inhibition of JNK, IRS-1, and tau phosphorylation. These data indicate JNK mediates Abeta oligomer inactivation of IRS-1 and phospho-tau pathology and that dietary treatment with fish oil/DHA, curcumin, or a combination of both has the potential to improve insulin/trophic signaling and cognitive deficits in AD.

The dysregulation of glycogen synthase kinase-3 (GSK3) has been implicated in Alzheimer disease (AD) pathogenesis and in Abeta-induced neurotoxicity, leading us to investigate it as a therapeutic target in an intracerebroventricular Abeta infusion model. Infusion of a specific GSK3 inhibitor SB216763 (SB) reduced a downstream target, phospho-glycogen synthase 39%, and increased glycogen levels 44%, suggesting effective inhibition of enzyme activity. Compared to vehicle, Abeta increased GSK3 activity, and was associated with elevations in levels of ptau, caspase-3, the tau kinase phospho-c-jun N-terminal kinase (pJNK), neuronal DNA fragmentation, and gliosis. Co-infusion of SB corrected all responses to Abeta infusion except the induction of gliosis and behavioral deficits in the Morris water maze. Nevertheless, SB alone was associated with induction of neurodegenerative markers and behavioral deficits. These data support a role for GSK3 hyperactivation in AD pathogenesis, but emphasize the importance of developing inhibitors that do not suppress constitutive activity.

Defects in dendritic spines and synapses contribute to cognitive deficits in mental retardation syndromes and, potentially, Alzheimer disease. p21-activated kinases (PAKs) regulate actin filaments and morphogenesis of dendritic spines regulated by the Rho family GTPases Rac and Cdc42. We previously reported that active PAK was markedly reduced in Alzheimer disease cytosol, accompanied by downstream loss of the spine actin-regulatory protein Drebrin. beta-Amyloid (Abeta) oligomer was implicated in PAK defects. Here we demonstrate that PAK is aberrantly activated and translocated from cytosol to membrane in Alzheimer disease brain and in 22-month-old Tg2576 transgenic mice with Alzheimer disease. This active PAK coimmunoprecipitated with the small GTPase Rac and both translocated to granules. Abeta42 oligomer treatment of cultured hippocampal neurons induced similar effects, accompanied by reduction of dendrites that were protected by kinase-active but not kinase-dead PAK. Abeta42 oligomer treatment also significantly reduced N-methyl-d-aspartic acid receptor subunit NR2B phosphotyrosine labeling. The Src family tyrosine kinase inhibitor PP2 significantly blocked the PAK/Rac translocation but not the loss of p-NR2B in Abeta42 oligomer-treated neurons. Src family kinases are known to phosphorylate the Rac activator Tiam1, which has recently been shown to be Abeta-responsive. In addition, anti-oligomer curcumin comparatively suppressed PAK translocation in aged Tg2576 transgenic mice with Alzheimer amyloid pathology and in Abeta42 oligomer-treated cultured hippocampal neurons. Our results implicate aberrant PAK in Abeta oligomer-induced signaling and synaptic deficits in Alzheimer disease.

Non-steroidal anti-inflammatory agents (NSAIDs) are associated with a marked reduction in the risk of developing Alzheimer's disease, a form of dementia characterized by the accumulation of amyloid plaques containing the amyloid-beta protein (Abeta). Studies of the effects of NSAIDs upon the inflammatory response surrounding amyloid plaques and upon the generation of Abeta from the amyloid precursor protein (APP) have led to two proposed mechanisms by which NSAIDs may protect against Alzheimer's disease: one, the selective lowering of Abeta42 by a subset of NSAIDs; and two, the reduction of inflammation. Although Alzheimer's disease is a disorder of brain and synaptic function, the effects of NSAIDs on Abeta-mediated suppression of synaptic plasticity and memory function have never been reported. We therefore investigated how three different NSAIDs, chosen for their distinct effects on Abeta42 production and the inhibition of the cyclooxygenase (COX) isoenzymes, COX-1 and COX-2, affect memory function and synaptic plasticity. By focusing upon brain and synapse function, we made novel observations about the effects of NSAIDs on Abeta-mediated neural processes. Here we report that the selective inhibition of COX-2, but not COX-1, acutely prevented the suppression of hippocampal long-term plasticity (LTP) by Abeta. The non-selective NSAIDs, ibuprofen and naproxen, and a selective COX-2 inhibitor, MF-tricyclic, each restored memory function in Tg2576 mice over-expressing APP, and also blocked Abeta-mediated inhibition of LTP. There was no advantage of ibuprofen, a selective Abeta42-lowering agent (SALA), over the non-SALAs, naproxen and MF-tricyclic. The beneficial effects on memory did not depend upon lowered levels of Abeta42 or the inflammatory cytokines, tumour necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta). Intriguingly, improved memory function was inversely related to prostaglandin E2 (PGE2) levels. Conversely, exogenous PGE2 prevented the restorative effects of COX-2 inhibitors on LTP. The data indicate that the inhibition of COX-2 blocks Abeta-mediated suppression of LTP and memory function, and that this block occurs independently of reductions in Abeta42 or decreases in inflammation. The results lead us to propose a third possible mechanism by which NSAIDs may protect against Alzheimer's disease, involving the blockade of a COX-2-mediated PGE2 response at synapses.

Environmental and genetic factors, notably ApoE4, contribute to the etiology of late-onset Alzheimer's disease (LOAD). Reduced mRNA and protein for an apolipoprotein E (ApoE) receptor family member, SorLA (LR11) has been found in LOAD but not early-onset AD, suggesting that LR11 loss is not secondary to pathology. LR11 is a neuronal sorting protein that reduces amyloid precursor protein (APP) trafficking to secretases that generate β-amyloid (Aβ). Genetic polymorphisms that reduce LR11 expression are associated with increased AD risk. However these polymorphisms account for only a fraction of cases with LR11 deficits, suggesting involvement of environmental factors. Because lipoprotein receptors are typically lipid-regulated, we postulated that LR11 is regulated by docosahexaenoic acid (DHA), an essential ω-3 fatty acid related to reduced AD risk and reduced Aβ accumulation. In this study, we report that DHA significantly increases LR11 in multiple systems, including primary rat neurons, aged non-Tg mice and an aged DHA-depleted APPsw AD mouse model. DHA also increased LR11 in a human neuronal line.In vivoelevation of LR11 was also observed with dietary fish oil in young rats with insulin resistance, a model for type II diabetes, another AD risk factor. These data argue that DHA induction of LR11 does not require DHA-depleting diets and is not age dependent. Because reduced LR11 is known to increase Aβ production and may be a significant genetic cause of LOAD, our results indicate that DHA increases in SorLA/LR11 levels may play an important role in preventing LOAD.

Extracellular-signal regulated kinase (ERK) signaling is critical for memory and tightly regulated by acute environmental stimuli. In Alzheimer disease transgenic models, active ERK is shown to first be increased, then later reduced, but whether these baseline changes reflect disruptions in ERK signaling is less clear. We investigated the influence of the familial Alzheimer's disease transgene APPsw and beta-amyloid peptide (Abeta) immunoneutralization on cannulation injury-associated (i.c.v. infusion) ERK activation. At both 12 and 22 months of age, the trauma-associated activation of ERK observed in Tg(-) mice was dramatically attenuated in Tg(+). In cortices of 22-month-old non-infused mice, a reduction in ERK activation was observed in Tg(+), relative to Tg(-) mice. Intracerebroventricular (i.c.v.) anti-Abeta infusion significantly increased phosphorylated ERK, its substrate cAMP-response element-binding protein (CREB) and a downstream target, the NMDA receptor subunit. We also demonstrated that Abeta oligomer decreased active ERK and subsequently active CREB in human neuroblastoma cells, which could be prevented by oligomer immunoneutralization. Abeta oligomers also inhibited active ERK and CREB in primary neurons, in addition to reducing the downstream post-synaptic protein NMDA receptor subunit. These effects were reversed by anti-oligomer. Our data strongly support the existence of an APPsw transgene-dependent and Abeta oligomer-mediated defect in regulation of ERK activation.

Studies in animals clearly show that oral intake of docosahexaenoic acid (DHA) can alter brain DHA concentrations and thereby modify brain functions. This provides us with an opportunity to use DHA as a nutraceutical or pharmaceutical tool in brain disorders such as Alzheimer disease (AD) and Parkinson disease (PD). Most of the published epidemiological studies are consistent with a positive association between high reported DHA consumption or high DHA blood levels and a lower risk of developing AD later in life. Such observations have prompted the investigation of DHA in three different transgenic models of AD. These analyses show that animal models of AD are more vulnerable to DHA depletion than controls and that DHA exerts a beneficial effect against pathological signs of AD, including A beta accumulation, cognitive impairment, synaptic marker loss, and hyperphosphorylation of tau. Multiple mechanisms of action can be associated with the neuroprotective effects of DHA and include antioxidant properties and activation of distinct cell signaling pathways. Although the first randomized clinical assays have yet failed to demonstrate convincing beneficial effects of DHA for AD patients, the knowledge gathered in recent years holds out a hope for prevention and suggests that the elderly and people bearing a genetic risk for AD should at least avoid DHA deficiency.

Although increased lifespan is associated with reduced insulin signaling, insulin signaling is essential for neuronal development and survival. Insulin resistance is central to Type II diabetes and is also implicated in the pathogenesis of Alzheimer’s Disease (AD). This has prompted ongoing clinical trials in AD patients to test the efficacy of improving insulin – like signaling with dietary ω-3 fatty acids or insulin – sensitizing drugs as well as exercise regimens. Here we review the role of insulin signaling in brain aging and AD, concluding that the signaling pathways downstream to neurotrophic and insulin signaling are defective and coincident with aberrant phosphorylation and translocation of key components, notably AKT and GSK3β, but also rac> PAK signaling. These responses are likely to contribute to defects in synaptic plasticity, learning and memory. Both oligomers of β-amyloid (which are elevated in the AD brain) and pro-inflammatory cytokines (which are elevated in the aged or AD brain) can be used to mimic the trophic factor/insulin resistance observed in AD, but details on other factors and mechanisms contributing to this resistance remain elusive. A better understanding of the precise mechanisms underlying alterations in the insulin/neurotrophic factor signal transduction pathways should aid the search for better AD therapeutic and prevention strategies.

Objective: We investigated the association between apoE protein plasma levels and brain amyloidosis and the effect of the top 10 Alzheimer disease (AD) risk genes on this association. Methods: Our dataset consisted of 18 AD, 52 mild cognitive impairment, and 3 cognitively normal Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) participants with available [11C]-Pittsburgh compound B (PiB) and peripheral blood protein data. We used cortical pattern matching to study associations between plasma apoE and cortical PiB binding and the effect of carrier status for the top 10 AD risk genes. Results: Low plasma apoE was significantly associated with high PiB SUVR, except in the sensorimotor and entorhinal cortex. For BIN1 rs744373, the association was observed only in minor allele carriers. For CD2AP rs9349407 and CR1 rs3818361, the association was preserved only in minor allele noncarriers. We did not find evidence for modulation by CLU, PICALM, ABCA7, BIN1, and MS4A6A. Conclusions: Our data show that BIN1 rs744373, CD2AP rs9349407, and CR1 rs3818361 genotypes modulate the association between apoE protein plasma levels and brain amyloidosis, implying a potential epigenetic/downstream interaction.

Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment but strongly interacts with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on micro- and astroglia and trigger an innate immune response, characterized by the release of inflammatory mediators, which contribute to disease progression and severity. Genome wide analysis suggests that several genes, which increase the risk for sporadic Alzheimer's disease en-code for factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity are likely to interfere with the immunological processes of the brain and further promote disease progression. This re-view provides an overview on the current knowledge and focuses on the most recent and exciting findings. Modulation of risk factors and intervention with the described immune mechanisms are likely to lead to future preventive or therapeutic strategies for Alzheimer's disease.

Although active and passive immunization against the beta-amyloid peptide (Abeta) of amyloid plaque-bearing transgenic mice markedly reduces amyloid plaque deposition and improves cognition, the mechanisms of neuroprotection and impact on toxic oligomer species are not understood. We demonstrate that compared to control IgG2b, passive immunization with intracerebroventricular (icv) anti-Abeta (1-15) antibody into the AD HuAPPsw (Tg2576) transgenic mouse model reduced specific oligomeric forms of Abeta, including the dodecamers that correlate with cognitive decline. Interestingly, the reduction of soluble Abeta oligomers, but not insoluble Abeta, significantly correlated with reduced tau phosphorylation by glycogen synthase kinase-3beta (GSK-3beta), a major tau kinase implicated previously in mediating Abeta toxicity. A conformationally-directed antibody against amyloid oligomers (larger than tetramer) also reduced Abeta oligomer-induced activation of GSK3beta and protected human neuronal SH-SY5Y cells from Abeta oligomer-induced neurotoxicity, supporting a role for Abeta oligomers in human tau kinase activation. These data suggest that antibodies that are highly specific for toxic oligomer subspecies may reduce toxicity via reduction of GSK-3beta, which could be an important strategy for Alzheimer's disease (AD) therapeutics.

Insulin-degrading enzyme (IDE) is one of the proteins that has been demonstrated to play a key role in degrading β-amyloid (Aβ) monomerin vitroandin vivo, raising the possibility of upregulating IDE as an approach to reduce Aβ. Little is known, however, about the cellular and molecular regulation of IDE protein. Because one of the main functions of IDE is to degrade insulin, we hypothesized that there is a negative feedback mechanism whereby stimulation of insulin receptor-mediated signaling upregulates IDE to prevent chronic activation of the pathway. We show that treatment of primary hippocampal neurons with insulin increased IDE protein levels by ∼25%. Insulin treatment also led to phosphatidylinositol-3 (PI3) kinase activation evidenced by Akt phosphorylation, which was blocked by PI3 kinase inhibitors, wortmannin and LY 294002. Inhibition of PI3 kinase abolished the IDE upregulation by insulin, indicating a cause-effect relationship between insulin signaling and IDE upregulation. Further support for this link was provided by the findings that deficient insulin signaling (decreased PI3 kinase subunit P85) was correlated with reduced IDE in Alzheimer's disease (AD) brains and in Tg2576 Swedish amyloid precursor protein transgenic mice fed a safflower oil-enriched (“Bad”) diet used to accelerate pathogenesis. Consistent with IDE function in the degradation of Aβ monomer, the IDE decrease in the Bad diet-fed Tg2576 mice was associated with increased Aβ monomer levels. Thesein vitroandin vivoanalyses validate the use of enhanced CNS insulin signaling as a potential strategy for AD intervention to correct the IDE defects occurring in AD.

Both oxidative damage and inflammation are elevated in brains of Alzheimer's disease (AD) patients, but their pathogenic significance remains unclear. The reduced AD risk associated with high intake of both nonsteroidal anti-inflammatory drugs (NSAIDs) and antioxidants suggests causal roles, but clinical trials in AD patients have yielded only limited or negative results. To test the potential efficacy and mechanisms of candidate approaches, we have explored conventional and unconventional NSAIDs, antioxidants, and combined NSAID/antioxidants in cell culture and animal models for AD (including aging APPsw transgenic mice and soluble Abeta rodent infusion models). The conventional NSAID ibuprofen has the strongest epidemiological support. At sustainable doses designed to mimic protective consumption in the epidemiology, ibuprofen reduces amyloid accumulation but suppresses a surprisingly limited subset of inflammatory markers in APPsw transgenic mice. Both Ab production (APP, beta- and gamma-secretases) and post-production pathways (those affecting Abeta aggregation or clearance: e.g., IL-1 or alpha1ACT) are potentially involved in ibuprofen and other NSAID anti-AD activities. The post-production pathways are predictably shared with other seemingly protective NSAIDs, including naproxen that do not lower Abeta42 in vitro. Using clinically feasible dosing, brain levels of NSAIDs appear too low to implicate a number of pharmacological dose targets that have been demonstrated in vitro. Ibuprofen did not suppress microglial markers related to phagocytosis. The putative anti-inflammatory omega-3 fatty acid DHA had a profound impact on pathogenesis but did not lower inflammation, while vitamin E was surprisingly ineffective in reducing oxidative damage or amyloid in the aged APPsw mouse. In contrast, the unconventional NSAID/antioxidant curcumin was effective, lowering oxidative damage, cognitive deficits, synaptic marker loss, and amyloid deposition. Curcumin proved to be immunomodulatory, simultaneously inhibiting cytokine and microglial activation indices related to neurotoxicity, but increasing an index of phagocytosis. Curcumin directly targeted Abeta and was also effective in other models, warranting further preclinical and clinical exploration.

Methods for cell type specific targeted intracellular delivery of proteins in vivo remain limited. A murine monoclonal anti-dsDNA antibody, mAb 3E10, was selectively transported into skeletal muscle cells in vivo. The antibody bound a 200 kDa protein only found in lysates of skeletal muscle by Western blotting. The 200 kDa protein was purified from muscle lysate by antibody affinity chromatography and identified as the skeletal muscle specific heavy chain of myosin IIb by electrospray mass spectrometry. Antibody binding specificity for myosin IIb was demonstrated in Western blots by binding myosin in skeletal muscle lysates from mice null for myosin IId but not in mice null for myosin IIb. Myosin IIb is implicated in the specific targeting of mAb 3E10 to skeletal muscle.

Non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with reduced risk for Alzheimer's disease (AD) and selected NSAIDs racemates suppress beta-amyloid (Abeta) accumulation in vivo and Abeta42 production in vitro. Clinical use of NSAIDs for preventing or treating AD has been hampered by dose-limiting toxicity believed to be due to cyclooxygenase (COX)-inhibition that is reportedly not essential for selective Abeta42 reduction. Profens have racemates and R-enantiomers were supposed to be inactive forms. Here we demonstrate that R-ibuprofen and R-flurbiprofen, with poor COX-inhibiting activity, reduce Abeta42 production by human cells. Although these R-enantiomers inhibit nuclear factor-kappaB (NF-kappaB) activation and NF-kappaB can selectively regulate Abeta42, Abeta42 reduction is not mediated by inhibition of NF-kappaB activation. Because of its efficacy at lowering Abeta42 production and low toxicity profile, R-flurbiprofen is a strong candidate for clinical development.

The apolipoprotein E (apoE) epsilon 4 allele (apoE4) is a major risk factor for neurodegenerative conditions, including Alzheimer's disease (AD). A role for apoE in regeneration of synaptic circuitry after neural injury has been shown in several in vitro studies in which apoE3 supports neuronal sprouting better than apoE4. We evaluated sprouting in an in vitro mouse organotypic hippocampal slice culture system derived from transgenic mice expressing apoE3 or apoE4, in which apoE-dependent granule cell mossy fiber sprouting in the presence of apoE4 is only 51% of the level of apoE3. Sprouting supported by apoE4 had a dose response opposite that by supported by apoE3: although increasing E3 expression increased sprouting, increasing E4 expression decreased sprouting, suggesting that the defect in E4 in supporting neuronal sprouting is a gain-of-negative activity. These results may have important pharmacogenomic implications for AD therapies that modulate apoE expression levels.

International audience; Hyperphosphorylation and accumulation of tau aggregates are prominent features in tauopathies, including Alzheimer's disease, but the impact of loss of tau function on synaptic and cognitive deficits remains poorly understood. We report that old (19 - 20 months; OKO) but not middle-aged (8 - 9 months; MKO) tau knock-out mice develop Morris Water Maze(MWM) deficits and loss of hippocampal acetylated alpha-tubulin and excitatory synaptic proteins. Mild motor deficits and reduction in tyrosine hydroxylase (TH) in the substantia nigra were present by middle age, but did not affect MWM performance, whereas OKO mice showed MWM deficits paralleling hippocampal deficits. Deletion of tau, a microtubule-associated protein (MAP), resulted in increased levels of MAP1A, MAP1B, and MAP2 in MKO, followed by loss of MAP2 and MAP1B in OKO. Hippocampal synaptic deficits in OKO mice were partially corrected with dietary supplementation with docosahexaenoic acid (DHA) and both MWM and synaptic deficits were fully corrected by combining DHA with alpha-lipoic acid (ALA), which also prevented TH loss. DHA or DHA/ALA restored phosphorylated and total GSK3 beta and attenuated hyperactivation of the tau C-Jun N-terminal kinases (JNKs) while increasing MAP1B, dephosphorylated (active) MAP2, and acetylated alpha-tubulin, suggesting improved microtubule stability and maintenance of active compensatory MAPs. Our results implicate the loss of MAP function in age-associated hippocampal deficits and identify a safe dietary intervention, rescuing both MAP function and TH in OKO mice. Therefore, in addition to microtubule-stabilizing therapeutic drugs, preserving or restoring compensatory MAP function may be a useful new prevention strategy.

Both oxidative damage and inflammation have been implicated in age-related neurodegenerative diseases including Alzheimer's Disease (AD). The yellow curry spice, curcumin, has both antioxidant and anti-inflammatory activities which confer significant protection against neurotoxic and genotoxic agents. We used 22 month Sprague-Dawley (SD) rats to compare the effects of the conventional NSAID, ibuprofen, and curcumin for their ability to protect against amyloid beta-protein (Abeta)-induced damage. Lipoprotein carrier-mediated, intracerebroventricular infusion of Abeta peptides induced oxidative damage, synaptophysin loss, a microglial response and widespread Abeta deposits. Dietary curcumin (2000 ppm), but not ibuprofen, suppressed oxidative damage (isoprostane levels) and synaptophysin loss. Both ibuprofen and curcumin reduced microgliosis in cortical layers, but curcumin increased microglial labeling within and adjacent to Abeta-ir deposits. In a second group of middle-aged female SD rats, 500 ppm dietary curcumin prevented Abeta-infusion induced spatial memory deficits in the Morris Water Maze and post-synaptic density (PSD)-95 loss and reduced Abeta deposits. Because of its low side-effect profile and long history of safe use, curcumin may find clinical application for AD prevention.

Human perinatal hypoxic-ischemic brain injury is an important cause of death and morbidity. One relatively common pattern of perinatal injury involves selective neuronal death in the ventral gray matter of the pons and in the subiculum of the hippocampal formation, classically termed 'pontosubicular neuronal necrosis' (PSN). The vulnerable neurons undergo karyorrhectic condensation of their nuclear chromatin and exhibit in situ end labeling for DNA fragmentation, leading to the recent reclassification of cell death in PSN as apoptotic. Caspase activation plays a central role in apoptosis and caspase-3 appears to be an especially important effector enzyme in neuronal apoptosis. In this study we performed immunohistochemistry on brain sections from six postmortem cases of PSN using two polyclonal antisera; CM1, a specific marker of caspase-3 activation, and fractin, which specifically recognizes a neoepitope at a caspase cleavage site in actin, and is therefore a marker of caspase-like proteolytic activity. Numerous CM1- and fractin-immunolabeled neurons were seen in the nuclei pontis and subiculum in each case, and the great majority showed karyorrhectic morphology. The immunostaining involved the nuclei and cytoplasm of these cells and the proximal portions at least of their neuritic processes. Some neurons exhibited a more extensive pattern of dendritic fractin labeling. Frequent CM1- and fractin-immunoreactive axonal segments were also seen. The identification of caspase-3 activation and caspase-like proteolytic activity in PSN cases in this study suggests that caspase inhibitors may potentially have a therapeutic neuroprotective role in human perinatal hypoxic-ischemic brain injury.

A prominent feature of neurodegenerative diseases is a loss of specific neuronal populations. The pathophysiological mechanisms responsible are, however, poorly understood. Primary cultures of rodent embryonic neurons represent a useful experimental system for investigation of molecular pathways of neurodegeneration and mechanisms of cell death. Here, we report a technique utilizing triple-label immunocytochemistry with confocal immunofluorescence detection designed to simultaneously assess multiple parameters of cell injury in individual hippocampal neurons in primary culture. This method combines detection of DNA damage (TUNEL or Klenow assay) with double-label immunocytochemistry for the activated form of caspase-3 or, alternatively, caspase-cleaved actin (fractin), and microtubule-associated protein-2 (MAP-2) or β-tubulin. The combined evaluation of the form of nuclear damage (karyorrhexis, pyknosis), the presence or absence of activated caspase-3, and the extent of the damage to cell cytoskeleton, allows for precise assessment of the extent of injury and the mode of cell death (apoptosis, oncosis) for individual neurons.

Retinal cell death induced by over-stimulation of glutamate receptors is related to the programmed cell death or apoptosis. However, little is known about the intracellular events that lead to this cell death process in the retina. In this study, we asked if caspase-3 family cysteine proteases regulate cell death in an explant culture of adult rat retina after exposure to excessive glutamate. Cells with DNA fragmentation were first detected in the ganglion cell layer 3 h after a brief exposure to 20 mM glutamate; whilst those in the inner nuclear layer were first observed 6 h after the glutamate lesion. Caspase-3-like activity, as indicated by immunostaining of the fractin antibody that recognizes actin fragments generated by caspase-3 family proteases, was seen 40 min after glutamate treatment. Staining was first detected in the ganglion cell layer and then in the inner nuclear layer, preceding the appearance of cells with DNA fragmentation in these layers. Colocalization study showed that all cells with DNA breaks were fractin positive, indicating that caspase-3 family activity was involved in the glutamate-induced cell death in the adult rat retina. Furthermore, DEVD-CHO, a tetrapeptide inhibitor for caspase-3 family members, reduced dramatically the fractin staining and significantly alleviated glutamate-induced cell death and DNA fragmentation in the ganglion cell layer and inner nuclear layer. Inhibitor for caspase-1-like activity, YVAD-CHO, neither reduced the fractin staining nor showed comparable neuroprotective effects to the retina. We conclude that glutamate-induced apoptotic cell death in adult rat retina is mediated by a specific activation of cysteine proteases related to the caspase-3 family, and an intervention to the caspase-3 proteases provides effective protection to retinal neurons against glutamate excitotoxicity.

The brain in Alzheimer's disease (AD) shows a chronic inflammatory response characterized by activated glial cells and increased expression of cytokines and complement factors surrounding amyloid deposits. Several epidemiological studies have demonstrated a reduced risk for AD in patients using nonsteroidal anti-inflammatory drugs (NSAIDs), prompting further inquiries about how NSAIDs might influence the development of AD pathology and inflammation in the CNS. We tested the impact of chronic orally administered ibuprofen, the most commonly used NSAID, in a transgenic model of AD displaying widespread microglial activation, age-related amyloid deposits, and dystrophic neurites. These mice were created by overexpressing a variant of the amyloid precursor protein found in familial AD. Transgene-positive (Tg+) and negative (Tg−) mice began receiving chow containing 375 ppm ibuprofen at 10 months of age, when amyloid plaques first appear, and were fed continuously for 6 months. This treatment produced significant reductions in final interleukin-1β and glial fibrillary acidic protein levels, as well as a significant diminution in the ultimate number and total area of β-amyloid deposits. Reductions in amyloid deposition were supported by ELISA measurements showing significantly decreased SDS-insoluble Aβ. Ibuprofen also decreased the numbers of ubiquitin-labeled dystrophic neurites and the percentage area per plaque of anti-phosphotyrosine-labeled microglia. Thus, the anti-inflammatory drug ibuprofen, which has been associated with reduced AD risk in human epidemiological studies, can significantly delay some forms of AD pathology, including amyloid deposition, when administered early in the disease course of a transgenic mouse model of AD.

Hirano bodies are eosinophilic rod-like inclusions that are found predominantly in neuronal processes in the hippocampal CA1 sector with increasing age and are particularly numerous in Alzheimer's disease. They contain a variety of cytoskeletal epitopes, especially actin and actin-binding proteins. Actin cleavage by cysteinyl aspartate-specific proteases (caspases) is a feature of apoptosis. Cleavage at aspartate 244 generates N-terminal 32 kDa and C-terminal 15 kDa actin fragments. This has led to the development of a rabbit polyclonal antibody specific for caspase-cleaved actin, directed to the last five C-terminal amino acids of the 32 kDa fragment of actin ('fractin'). Fractin immunohistochemistry was performed on hippocampal sections from Alzheimer's disease and control cases containing numerous Hirano bodies, in addition to immunolabelling with CM1 antiserum which recognizes activated caspase-3. The Hirano bodies showed strong diffuse fractin immunoreactivity. They did not label with CM1 antiserum, perhaps reflecting too low a level of activated caspase-3 for immunodetection, or involvement of a different member of the caspase family. The finding of fractin immunoreactivity of Hirano bodies suggests that caspase-like cleavage of actin may play a role in their formation and further supports caspase-like activity in neuronal processes, distinct from that associated with acute perikaryal apoptosis.

beta-Amyloid (Abeta) deposits are found in the brains of approximately one-third of patients who die within days after a severe head injury; their presence correlating strongly with possession of an apolipoprotein E (apoE)-epsilon4 allele. The aim of the study was to investigate the relationship between Abeta42, Abeta40 and apoE immunostaining of Abeta plaques in the cerebral cortex and the relevance of apoE genotype in 23 fatally head-injured patients. These cases were known to have Abeta deposits from a previous study in which they were examined and semiquantified and related to apoE genotype. In the present study, the temporal cortex was probed using four different antibodies that recognize Abeta42(43), Abeta40 and an antibody to apoE. Abeta42(43)-positive plaques were observed in all of the 23 cases and Abeta40 immunoreactivity in only 11 of the 23 cases. In addition, semiquantitative analysis showed that relatively fewer plaques were detected with anti-Abeta40 than anti-Abeta42(43). ApoE-immunoreactive plaques were identified in 18 of the 23 cases. The number of plaques stained for apoE was relatively less than for Abeta42(43) but greater than for Abeta40. Furthermore, the density of Abeta plaques detected using either Abeta42(43), Abeta40 or apoE antibodies was associated with possession of apoE-epsilon4 in an allele dose-dependent manner. The results are consistent with Abeta42(43) as the initially deposited species in brain parenchyma and provide evidence that apoE is involved in the early stages of amyloid deposition. Further, the findings may be of relevance to the role of apoE genotype in influencing outcome after acute brain injury.

Amyloid beta-protein (Abeta), the major component of plaques in Alzheimer's disease, is a small hydrophobic protein that is carried on apolipoprotein E (ApoE)- and ApoJ-containing lipoprotein particles in plasma and cerebrospinal fluid (CSF). Microglia, the scavenger cells of the CNS, take up and degrade Abeta via lipoprotein receptors including scavenger receptors A and B, and possibly via other receptors. Lipoproteins, ApoE, and ApoJ influence the uptake and degradation of Abeta in vitro and in vivo. Differences in ApoE-E4, -E3, and -E2 isoforms with respect to Abeta binding to lipoproteins and delivery to cells, including microglia, may contribute to the increased risk of Alzheimer's disease for people with an APOE4 genotype and to risk reduction with APOE2.

An inflammatory response involving activated microglia in neuritic beta-amyloid plaques is found in Alzheimer's disease (AD) brain. Because HDL lipoproteins have been shown to carry the beta-amyloid peptide (Abeta) in plasma and CSF, we have investigated the influence of plasma high-density lipoprotein (HDL) and lipidated ApoE and ApoJ particles on the interaction of cultured rat microglia with Abeta1-42. Microglia degraded Abeta via a pathway sensitive to cytochalasin D and the scavenger receptor inhibitor, fucoidan. HDL increased the degradation of Abeta and the ratio of multimeric/monomeric Abeta in a dose-dependent manner. In contrast, lipidated ApoJ and ApoE decreased the degradation of Abeta, and the effects were ApoE isoform-dependent. Immuno-electron microscopy revealed internalized Abeta in endosomes and lysosomes as well as cell-associated Abeta in deep invaginations, which may be related to caveolae and surface-connected compartments. These data suggest that lipoprotein-dependent Abeta trafficking to microglia could be relevant to plaque pathogenesis in AD.

A role for apolipoprotein E is implicated in regeneration of synaptic circuitry after neural injury. The in vitro mouse organotypic hippocampal slice culture system shows Timm's stained mossy fiber sprouting into the dentate gyrus molecular layer in response to deafferentation of the entorhinal cortex. We show that cultures derived from apolipoprotein E knockout mice are defective in this sprouting response; specifically, they show no sprouting in the dorsal region of the dentate gyrus, yet retain sprouting in the ventral region. Dorsal but not ventral sprouting in cultures from C57B1/6J mice is increased 75% by treatment with 100 pM 17beta-estradiol; this response is blocked by both progesterone and tamoxifen. These results show that neuronal sprouting is increased by estrogen in the same region where sprouting is dependent on apolipoprotein E. Sprouting may be stimulated by estrogen through its up-regulation of apolipoprotein E expression leading to increased recycling of membrane lipids for use by sprouting neurons. Estrogen and apolipoprotein E may therefore interact in their modulation of both Alzheimer's disease risk and recovery from CNS injury.

Background and Purpose —The mechanisms of excitotoxic cell death in cerebral ischemia are poorly understood. In addition to necrosis, apoptotic cell death may occur. The purpose of this study was to determine whether an established model of cerebral hypoxia-ischemia in the neonatal rat demonstrates any features of apoptosis. Methods —Seven-day-old neonatal rats underwent bilateral, permanent carotid ligation followed by 1 hour of hypoxia, and their brains were examined 1, 3, and 4 days after hypoxia-ischemia. The severity of ischemic damage was assessed in the dentate gyrus and frontotemporal cortex by light microscopy. Immunocytochemistry was performed to detect the cleavage of actin by caspases, a family of enzymes activated in apoptosis. Terminal deoxynucleotidyl transferase–mediated dUTP-biotin nick end labeling (TUNEL) reactivity was examined in the cortical infarction bed and dentate gyrus. Neonatal rat brain DNA was run on agarose gel electrophoresis to detect DNA fragmentation. Ethidium bromide–staining and electron microscopy were used to determine whether apoptotic bodies, 1 of the hallmarks of apoptosis, were present. Results —The frontotemporal cortex displayed evidence of infarction, and in most rats the dentate gyrus showed selective, delayed neuronal death. Immunocytochemistry demonstrated caspase-related cleavage of actin. TUNEL and DNA electrophoresis provided evidence of DNA fragmentation. Ethidium bromide–staining and electron microscopy confirmed the presence of chromatin condensation and apoptotic bodies. Conclusions —Features of apoptosis are present in the described model of cerebral hypoxia-ischemia. Apoptosis may represent a mode of ischemic cell death that could be the target of novel treatments that could potentially expand the therapeutic window for stroke.

Among a variety of neurodegenerative diseases, Alzheimer’s disease (AD) and Huntington’s disease (HD) have been particularly well studied at the genetic and molecular levels. The progressive cognitive decline in AD patients is known to be most closely associated with the pathological signature amyloid-β (Aβ) protein deposited in extracellular plaques and intraneuronal neurofibrillary tangles (NFT) consisting largely of tau protein. AD is heterogeneous and can be caused either by rare autosomal dominant mutations elevating aggregation-prone Aβ or by a mix of environmental and genetic risk factors. In contrast, the sole known genetic cause of HD is mutations of the huntingtin gene that lead to the oligomerization of its gene product (huntingtin) with extra oligoGln (also called polyQ) resulting in neurotoxicity. Loss of synapses and dendritic spines in vulnerable areas are early pathological indices related to cognitive deficits in various neurodegenerative diseases, including AD and HD. Aβ aggregates activate GTPases, RAC and CDC42 via Tiam 1 in a Ca 2+- dependent manner, and these GTPases in turn activate the kinase PAK1, which directly activates LIM kinase (LIMK). LIMK inactivates cofilin and F-actin severing protein, and eventually stimulates actin polymerization, disrupting actin dynamics, which can lead to the formation of actin rods and disruption of dendritic spines. Imbalances in actin dynamics can also occur in other cell types, such as through influencing actomyosin-dependent phagocytosis of neurons by microglia. The SRC family Tyr kinase inhibitor PP2, as well as curcumin, block PAK1 activation in Aβ oligomer-treated neurons. Similarly, in HD models, PAK1 activation enhances polyQ oligomerization and neurotoxicity. We discuss the potential of PAK1 as a viable target for the therapy of both AD and HD.

The mechanisms underlying Tau-related synaptic and cognitive deficits and the interrelationships between Tau species, their clearance pathways, and synaptic impairments remain poorly understood. To gain insight into these mechanisms, we examined these interrelationships in aged non-mutant genomic human Tau mice, with established Tau pathology and neuron loss. We also examined how these interrelationships changed with an intervention by feeding mice either a control diet or one containing the brain permeable beta-amyloid and Tau aggregate binding molecule curcumin. Transgene-dependent elevations in soluble and insoluble phospho-Tau monomer and soluble Tau dimers accompanied deficits in behavior, hippocampal excitatory synaptic markers, and molecular chaperones (heat shock proteins (HSPs)) involved in Tau degradation and microtubule stability. In human Tau mice but not control mice, HSP70, HSP70/HSP72, and HSP90 were reduced in membrane-enriched fractions but not in cytosolic fractions. The synaptic proteins PSD95 and NR2B were reduced in dendritic fields and redistributed into perikarya, corresponding to changes observed by immunoblot. Curcumin selectively suppressed levels of soluble Tau dimers, but not of insoluble and monomeric phospho-Tau, while correcting behavioral, synaptic, and HSP deficits. Treatment increased PSD95 co-immunoprecipitating with NR2B and, independent of transgene, increased HSPs implicated in Tau clearance. It elevated HSP90 and HSC70 without increasing HSP mRNAs; that is, without induction of the heat shock response. Instead curcumin differentially impacted HSP90 client kinases, reducing Fyn without reducing Akt. In summary, curcumin reduced soluble Tau and elevated HSPs involved in Tau clearance, showing that even after tangles have formed, Tau-dependent behavioral and synaptic deficits can be corrected. Background: Various types of Tau aggregates in AD brains may differentially impact neurodegeneration. Results: Curcumin selectively suppresses soluble Tau dimers and corrects molecular chaperone, synaptic, and behavioral deficits. Conclusion: A drug increasing HSPs involved in Tau clearance reduced Tau dimers and improved cognition. Significance: Curcumin that reduced Tau dimers and increased molecular chaperones was efficacious without altering insoluble Tau.

Objective To study the effect of familial Alzheimer disease (FAD) mutations and APOE genotype on plasma signaling protein levels. Design Cross-sectional comparison of plasma levels of 77 proteins measured using multiplex immune assays. Setting A tertiary referral dementia research center. Participants Thirty-three persons from families harboring PSEN1 or APP mutations, aged 19 to 59 years. Main Outcome Measures Protein levels were compared between FAD mutation carriers (MCs) and noncarriers (NCs) and among APOE genotype groups, using multiple linear regression models. Results Twenty-one participants were FAD MCs and 12 were NCs. Six had the APOE ϵ2/3, 6 had the ϵ3/4, and 21 had the ϵ3/3 genotype. Levels of 17 proteins differed among APOE genotype groups, and there were significant interactions between age and APOE genotype for 12 proteins. Plasma levels of apolipoprotein E and superoxide dismutase 1 were highest in the ϵ2 carriers, lowest in ϵ4 carriers, and intermediate in the ϵ3 carriers. Levels of multiple interleukins showed the opposite pattern and, among the ϵ4 carriers, demonstrated significant negative correlations with age. Although there were no significant differences between FAD MCs and NCs, there were interactions between mutation status and APOE genotype for 13 proteins. Conclusions We found different patterns of inflammatory markers in young and middle-aged persons among APOE genotype groups. The APOE ϵ4 carriers had the lowest levels of apolipoprotein E. Young ϵ4 carriers have increased inflammatory markers that diminish with age. We demonstrated altered inflammatory responses in young and middle adulthood in ϵ4 carriers that may relate to AD risk later in life.

Developmental cognitive deficits including X-linked mental retardation (XLMR) can be caused by mutations in P21-activated kinase 3 (PAK3) that disrupt actin dynamics in dendritic spines. Neurodegenerative diseases such as Alzheimer disease (AD), where both PAK1 and PAK3 are dysregulated, may share final common pathways with XLMR. Independent of familial mutation, cognitive deficits emerging with aging, notably AD, begin after decades of normal function. This prolonged prodromal period involves the buildup of amyloid-β (Aβ) extracellular plaques and intraneuronal neurofibrillary tangles (NFT). Subsequently region dependent deficits in synapses, dendritic spines and cognition coincide with dysregulation in PAK1 and PAK. Specifically proximal to decline, cytoplasmic levels of actin-regulating Rho GTPase and PAK1 kinase are decreased in moderate to severe AD, while aberrant activation and translocation of PAK1 appears around the onset of cognitive deficits. Downstream to PAK1, LIM kinase inactivates cofilin, contributing to cofilin pathology, while the activation of Rho-dependent kinase ROCK increases Aβ production. Aβ activation of fyn disrupts neuronal PAK1 and ROCK-mediated signaling, resulting in synaptic deficits. Reductions in PAK1 by the anti-amyloid compound curcumin suppress synaptotoxicity. Similarly other neurological disorders, including Huntington disease (HD) show dysregulation of PAKs. PAK1 modulates mutant huntingtin toxicity by enhancing huntingtin aggregation, and inhibition of PAK activity protects HD as well as fragile X syndrome (FXS) symptoms. Since PAK plays critical roles in learning and memory and is disrupted in many cognitive disorders, targeting PAK signaling in AD, HD and XLMR may be a novel common therapeutic target for AD, HD and XLMR.

Background/Aims: Biological markers of utility in tracking Alzheimer’s disease (AD) during the presymptomatic prodromal phase are important for prevention studies. Changes in cerebrospinal fluid (CSF) levels of 42-amino-acid β-amyloid (Aβ42), total tau protein (t-tau) and phosphorylated tau at residue 181 (p-tau181) during this state are incompletely characterized. Methods: We measured CSF markers in 13 carriers of familial AD (FAD) mutations that are fully penetrant for causing AD (PSEN1 and APP) and in 5 non-mutation-carrying family members. Results: Even among the entirely presymptomatic mutation carriers (n = 9), Aβ42 was diminished (388.7 vs. 618.4 pg/ml, p = 0.004), and t-tau (138.5 vs. 50.5 pg/ml, p = 0.002) and p-tau181 (71.7 vs. 24.6 pg/ml, p = 0.003) were elevated. There was a negative correlation between Aβ42 levels and age relative to the family-specific age of dementia diagnosis. Conclusions: Our data are consistent with a decline in CSF Aβ42 levels occurring at least 20 years prior to clinical dementia in FAD.

healthy elderly (age > 65) in WHICAP, a community-based and ethnically diverse cohort in New York. The associations between plasma As40 and As42 levels and calorie-adjusted dietary intake of 10 nutrients [saturated fatty acid (SFA), mono-unsaturated fatty acid (MUFA), u-3 poly-unsaturated fatty acid (PUFA), u-6 PUFA, vitamin E, vitamin C, s-carotene, vitamin B12, folate, and vitamin D], selected due to their potential association with dementia risk, were examined using linear regression models, first unadjusted and then adjusted for age, gender, ethnicity, education, and s-amyloid assessment wave. Results: In an unadjusted model that simultaneously included all 10 nutrients, higher intake of u-3 PUFA was significantly associated with lower As40 (s 1⁄4 -25.9, p1⁄40.001) and lower As42 (s1⁄4 -11.9, p1⁄40.001) levels; higher intake of MUFAwas significantly associated with lower As40 (s 1⁄4 -1.6, p1⁄40.046) and As42 (s 1⁄4 -0.8, p1⁄40.023) levels. In an adjusted model, u-3 retained a strong association with lower plasma levels of As42 (s 1⁄4-13.6, p1⁄40.045) and As40 (s 1⁄4 -7.2, p1⁄40.021), while MUFAwas no longer associated with As. Other nutrients did not seem to be significantly associated with plasma levels of either As40 or As42. Conclusions: In cognitively healthy elders, higher dietary intake of u-3 PUFA is associated with lower plasma levels of both As40 and As42 (which are markers of slower cognitive decline and lower dementia risk inour cohort). Thus, plasma s-amyloid may be related to dietary habits.