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Somatic mutations in mitochondrial DNA (mtDNA) are hypothesized to play a role in Parkinson disease (PD), but large increases in mtDNA mutations have not previously been found in PD, potentially because neurons with high mutation levels degenerate and thus are absent in late stage tissue. To address this issue, we studied early stage PD cases and cases of incidental Lewy body disease (ILBD), which is thought to represent presymptomatic PD. We show for the first time that mtDNA mutation levels in substantia nigra neurons are significantly elevated in this group of early PD and ILBD cases. Ann Neurol 2012;71:850-854 [ABSTRACT FROM AUTHOR]

Oxidative stress and mitochondrial dysfunction are important features present in Alzheimer's disease (AD). They appear early and contribute to disease progression, both in human postmortem AD brains as well as in transgenic AD mouse brains. For this reason, targeting oxidative stress and mitochondria in AD may lead to the development of promising therapeutic strategies. Several exogenous antioxidant compounds have been tested and found beneficial in transgenic AD mice, such as vitamins and spices. However, their efficacy was much more modest in human trials. More recently, new strategies have been elaborated to promote endogenous antioxidant systems. Different pathways involved in oxidative stress response have been identified. Compounds able to upregulate these pathways are being generated and tested in animal models of AD and in human patients. Upregulation of antioxidant gene expression was beneficial in mice, giving hope for future avenues in the treatment of AD and other neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative diseases. Mitochondria are critical regulators of cell death, a key feature of neurodegeneration. Mutations in mitochondrial DNA and oxidative stress both contribute to ageing, which is the greatest risk factor for neurodegenerative diseases. In all major examples of these diseases there is strong evidence that mitochondrial dysfunction occurs early and acts causally in disease pathogenesis. Moreover, an impressive number of disease-specific proteins interact with mitochondria. Thus, therapies targeting basic mitochondrial processes, such as energy metabolism or free-radical generation, or specific interactions of disease-related proteins with mitochondria, hold great promise. [ABSTRACT FROM AUTHOR]

Abstract: Somatic mitochondrial DNA (mtDNA) point mutations reach high levels in the brain. However, the cell types that accumulate mutations and the patterns of mutations within individual cells are not known. We have quantified somatic mtDNA mutations in 28 single neurons and in 18 single glia from post-mortem human substantia nigra of six control subjects. Both neurons and glia contain mtDNA with somatic mutations. Single neurons harbor a geometric mean (95% CI) of 200.3 (152.9–262.4) somatic mtDNA point mutations per million base pairs, compared to 133.8 (97.5–184.9) for single glia (p =0.0251). If mutations detected multiple times in the same cell are counted only once, the mean mutation level per million base pairs remains elevated in single neurons (146.9; 124.0–174.2) compared to single glia (100.5; 81.5–126.5; p =0.009). Multiple distinct somatic point mutations are present in different cells from the same subject. Most of these mutations are individually present at low levels (less than 10–20% of mtDNA molecules), but with high aggregate mutation levels, particularly in neurons. These mutations may contribute to changes in brain function during normal aging and neurodegenerative disorders. [Copyright &y& Elsevier]

Oxidative damage to mitochondrial DNA (mtDNA) increases with age in the brain and can induce G:C to T:A and T:A to G:C point mutations. Though rare at any particular site, multiple somatic mtDNA mutations induced by oxidative damage or by other mechanisms may accumulate with age in the brain and thus could play a role in aging and neurodegenerative diseases. However, no prior study has quantified the total burden of mtDNA point mutation subtypes in the brain. Using a highly sensitive cloning and sequencing strategy, we find that the aggregate levels of G:C to T:A and T:A to G:C transversions and of all point mutations increase with age in the frontal cortex (FCtx). In the substantia nigra (SN), the aggregate levels of point mutations in young controls are similar to the levels in the SN or FCtx of elderly subjects. Extrapolation from our data suggests an average of 2.7 (FCtx) to 3.2 (SN) somatic point mutations per mitochondrial genome in elderly subjects. There were no significant differences between Parkinson’s disease (PD) patients and age-matched controls in somatic mutation levels. These results indicate that individually rare mtDNA point mutations reach a high aggregate burden in FCtx and SN of elderly subjects. [Copyright &y& Elsevier]

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, which affects the anterior horn cells of the spinal cord and cortical motor neurons. A pathophysiological role for mtDNA mutations was postulated based on the finding that cybrids obtained from mitochondria of sporadic ALS patients exhibited impaired respiratory chain activities, increased free radical scavenging enzymes, and altered calcium homeostasis. To date, however, no distinct mtDNA alterations associated with ALS have been reported. Therefore, we reexamined the hypotheses that mtDNA mutations accumulate in ALS and that cybrids generated from ALS patients’ blood have impaired mitochondrial respiration. Cybrid cell lines were generated from 143B osteosarcoma ρ0 cells and platelet mitochondria of sporadic ALS patients or age-matched controls. We found no statistically significant differences in mitochondrial respiration between ALS and control cybrids, even when the electron transport chain was stressed with low concentrations of respiratory chain inhibitors. Mitochondrial respiratory chain enzyme activities were also normal in ALS cybrids, and there was no increase in free radical production. Therefore, we showed that mtDNA from platelets of ALS patients was able to restore normal respiratory function in ρ0 cells, suggesting that the presence of mtDNA mutations capable of affecting mitochondrial respiration was unlikely. [Copyright &y& Elsevier]

The oxidative stress theory of aging postulates that age-associated reductions in physiologic functions are caused by a slow steady accumulation of oxidative damage to macromolecules, which increases with age and which is associated with life expectancy of organisms. A corollary is that the rate of aging should be retarded by attenuation of oxidative damage. A large body of evidence has accumulated in support of this hypothesis. Increases in oxidative damage to DNA, proteins, and lipids have all been found with normal aging. Genetic manipulation of oxidative damage can increase life expectancy in animals. Overexpression of Cu/Zn superoxide dismutase or manganese superoxide dismutase appears to extend life span. Overexpression of methionine sulfoxide reductase in Drosophila resulted in a 70% increase in survival, and a 50% reduction in methionine sulfoxide reductase in mice resulted in a 30% reduction in life span. Caloric restriction, which extends life span, also reduces oxidative stress. Manipulation of gene expression in Drosophila with phenylbutyrate significantly increases lifespan, and is associated with a 50-fold increase in expression of manganese superoxide dismutase. We recently further examined the mitochondrial DNA theory of aging, which proposes that mitochondrial DNA accumulates mutations with age and that these contribute to the physiological decline in aging. Using a PCR-cloning-sequencing strategy, we found a significant increase in aggregate burden of mitochondrial DNA point mutations in brain in elderly subjects compared to younger subjects. The average aggregate mutational burden in elderly subjects was 2×10−4 mutations per base. The bulk of these mutations were individually rare point mutations, and 60% changed an amino acid. Cytochrome oxidase activity correlated negatively with increased mutational burden. These findings bolster the possibility that oxidative damage to mitochondrial DNA may play a significant role in normal aging. [Copyright &y& Elsevier]

Examines the 'gene gun' approach to cutaneous gene therapy. History of particle-mediated gene transfer; Mechanism in which the gene gun accelerates DNA-coated gold particles; Gene replacement; Genetic vaccination; Suicide gene therapy.

Current trials with amyloid antibodies have not shown clinical benefit, but the results suggest that treating patients earlier in the course, or during the presymptomatic period, might be beneficial. [ABSTRACT FROM AUTHOR]

The article presents a study by Anandatheerthavarada and others on the impairment of mitochondrial function in Alzheimer disease. The article discovers the presence of nonglycosylated full-length and C-terminally-truncated amyloid precursor protein (APP) associated with mitochondria in brain samples from Alzheimer disease patients. The article discusses the presence of higher levels of mitochondrial APP in more affected brain areas. The article concludes with the complicated effects of APP.

In a prospective, observational study in multiple centers in Italy, amyloid PET imaging was shown to be negative in 35% of patients who met clinical criteria for a diagnosis of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

An abstract of the article "Alzheimer's disease: Are blood and brain markers related? A systematic review" by Khan et al. is presented.

HIGHLY ACTIVE ANTI-RETROVIRAL THERAPY (HAART) has changed the nature of HIV dementia: the degree of cognitive impairment is milder, the course may improve as well as worsen, and traditional biomarkers such as CSF viral load or levels of monocyte chemotactic protein 1 (MCP-1) are less likely to be associated with dementia. The objective of this study was to identify new CSF biomarkers that are associated with or predictive of HIV dementia in the setting of HAART. The study involved 48 patients from the North Eastern AIDS Dementia cohort, assessed cognitively at 0, 6, and 12 months. CSF was drawn at the 6 month time point, and analyzed for biochemical markers. Biochemical markers correlating with cognitive change over the preceding 6 months (between 0 and 6 months) were said to be biomarkers associated with cognitive change; biochemical markers correlating with cognitive change over the subsequent 6 months (between 6 and 12 months) were said to be biomarkers predictive of cognitive change. Based on previous work showing accumulation of sphingomyelin, ceramide, sterol, and lipid peroxidation products in brains of HIV dementia patients, these were the primary biomarkers the authors investigated. Considering first the cognitive changes occurring before the CSF draw (between the 0 and 6 month time points), the authors divided the cohort into 3 groups: those who were not demented at both time points ("nondemented"), those who were initially demented and remained stably so ("inactive dementia"), and those who were initially not demented but became demented ("active dementia"). Those with inactive dementia over the preceding 6 months had 3-5 fold elevations of CSF sphingomyelin compared to nondemented or active dementia subjects. Those with active dementia over the preceding 6 months had increased CSF ceramide levels and sphingomyelinase activity, increased levels of lipid peroxidation products (4-hydroxynonenal), and decreased levels of the lipid antioxidant vitamin E. Considering, next, the cognitive changes occurring after the CSF draw (between the 6- and 12-month time points), the authors divided the cohort into 3 groups, based on whether scores improved, remained stable, or worsened. The group that subsequently worsened had increased CSF levels of triglyceride C52 and vitamin E. Sphingomyelin, ceramide, and hydroxynonenal levels were not predictive of subsequent worsening. [ABSTRACT FROM AUTHOR]

HYPERTENSION IS WELL ESTABLISHED AS A RISK FACTOR FOR vascular brain lesions. There is also emerging evidence that abnormal blood pressure may be a risk factor for neurodegeneration. Several cross-sectional studies have shown that high blood pressure in midlife is associated with more brain atrophy later in life, whereas in late life, low blood pressure is associated with more brain atrophy. However, there is little prospective evidence relating blood pressure and brain atrophy. The SMART-MR (Secondary Manifestations of ARTerial disease-Magnetic Resonance) study in the Netherlands is a prospective, cohort study on MRI brain changes in patients with arterial disease -- coronary artery disease, cerebrovascular disease, peripheral artery disease, or abdominal aortic aneurysm. Of 1309 patients enrolled from 2001-2005, 663 had MRIs at baseline and during follow-up from 2006-2009. Average follow-up time was 3.9 years, average age was 57, and 81% were men. The ventricular fraction was used as a measure of subcortical brain atrophy, and the ventricular fraction increased with time in all blood pressure groups. The key findings were 1) that in those with low diastolic blood pressure (DBP) at baseline, the increase in ventricular fraction was greater than in those with high DBP at baseline (this finding was driven primarily by patients with coronary artery disease); and 2) in those with normal or high DBP at baseline, the increase in ventricular fraction was less if DBP decreased over time than if it increased. Findings were adjusted for demographic factors, other vascular risk factors, alcohol consumption, baseline brain volume, and baseline burden of strokes and white matter lesions. Of note, previous studies found that low blood pressure was associated with increased brain atrophy in late life, whereas this study observed low DBP to be associated with increased brain atrophy in mid-life in patients with arterial disease. The authors hypothesized that patients with arterial disease have early vascular aging with increased arterial stiffness, impaired endothelial function, and impaired cerebral autoregulation, making them more vulnerable to low blood pressure. Because this association of low blood pressure and increased brain atrophy occurred primarily in patients with coronary artery disease, baseline low DBP might represent poor cardiac output and insufficient brain perfusion. On the other hand, in those with higher DBP at baseline, the association of decline in blood pressure over time with less brain atrophy suggests that treating abnormally high blood pressure will be beneficial. [ABSTRACT FROM AUTHOR]

Pathologic aggregation of β-amyloid (Aβ) peptide and the axonal microtubule-associated protein tau protein are hallmarks of Alzheimer's disease (AD). Evidence supports that Aβ peptide accumulation precedes microtubule-related pathology, although the link between Ab and tau remains unclear. We previously provided evidence for early co-localization of Aβ42 peptides and hyperphosphorylated tau within postsynaptic terminals of CA1 dendrites in the hippocampus of AD transgenic mice. Here, we explore the relation between Aβ peptide accumulation and the dendritic, microtubule-associated protein 2 (MAP2) in the well-characterized amyloid precursor protein Swedish mutant transgenic mouse (Tg2576). We provide evidence that localized intraneuronal accumulation of Aβ42 peptides is spatially associated with reductions of MAP2 in dendrites and postsynaptic compartments of Tg2576 mice at early ages. Our data support that reduction in MAP2 begins at sites of Aβ42 monomer and low molecular weight oligomer (M/LMW) peptide accumulation. Cumulative evidence suggests that accumulation of M/LMW Aβ42 peptides occurs early, before high molecular weight oligomerization and plaque formation. Since synaptic alteration is the best pathologic correlate of cognitive dysfunction in AD, the spatial association of M/LMW Aβ peptide accumulation with pathology of MAP2 within neuronal processes and synaptic compartments early in the disease process reinforces the importance of intraneuronal Aβ accumulation in AD pathogenesis. [ABSTRACT FROM AUTHOR]

A central question in Alzheimer's disease (AD) research is what role β-amyloid peptide (Aβ) plays in synaptic dysfunction. Synaptic activity increases Aβ secretion, potentially inhibiting synapses, but also decreases intraneuronal Aβ, protecting synapses. We now show that levels of secreted Aβ fall with time in culture in neurons of AD-transgenic mice, but not wild-type mice. Moreover, the ability of synaptic activity to elevate secretedAβ and reduce intraneuronalAβ becomes impaired in AD-transgenic but not wild-type neurons with time in culture. We demonstrate that synaptic activity promotes an increase in the Aβ-degrading protease neprilysin at the cell surface and a concomitant increase in colocalization with Aβ42. Remarkably, AD-transgenic but not wild-type neurons show reduced levels of neprilysin with time in culture. This impaired ability to secrete Aβ and reduce intraneuronal Aβ has important implications for the pathogenesis and treatment of AD. [ABSTRACT FROM AUTHOR]

Abstract: Although β-amyloid (Aβ) plaques and tau neurofibrillary tangles are hallmarks of Alzheimer''s disease (AD) neuropathology, loss of synapses is considered the best correlate of cognitive decline in AD, rather than plaques or tangles. How pathological Aβ and tau aggregation relate to each other and to alterations in synapses remains unclear. Since aberrant tau phosphorylation occurs in amyloid precursor protein (APP) Swedish mutant transgenic mice, and since neurofibrillary tangles develop in triple transgenic mice harboring mutations in APP, tau and presenilin 1, we utilized these well-characterized mouse models to explore the relation between Aβ and tau pathologies. We now report that pathological accumulation of Aβ and hyperphosphorylation of tau develop concomitantly within synaptic terminals. [Copyright &y& Elsevier]

A letter to the editor is presented regarding the case of a 39-year-old man who was admitted due to unsteadiness of gait and was diagnosed with Hashimoto's encephalopathy (HE) after physical and neurological examinations.

Increased oxidative stress is implicated in the pathogenesis of Alzheimer's disease (AD). A large body of evidence suggests that mitochondrial dysfunction and increased reactive oxygen species occur prior to amyloid-β (Aβ) deposition. Coenzyme Q10 (CoQ10), a component of the mitochondrial electron transport chain, is well characterized as a neuroprotective antioxidant in animal models and human trials of Huntington's disease and Parkinson's disease, and reduces plaque burden in AβPP/PS1 mice. We now show that CoQ10 reduces oxidative stress and amyloid pathology and improves behavioral performance in the Tg19959 mouse model of AD. CoQ10 treatment decreased brain levels of protein carbonyls, a marker of oxidative stress. CoQ10 treatment resulted in decreased plaque area and number in hippocampus and in overlying cortex immunostained with an Aβ42-specific antibody. Brain Aβ42 levels were also decreased by CoQ10 supplementation. Levels of amyloid-β protein precursor (AβPP) β-carboxyterminal fragments were decreased. Importantly, CoQ10-treated mice showed improved cognitive performance during Morris water maze testing. Our results show decreased pathology and improved behavior in transgenic AD mice treated with the naturally occurring antioxidant compound CoQ10. CoQ10 is well tolerated in humans and may be promising for therapeutic trials in AD. [ABSTRACT FROM AUTHOR]

Increased oxidative stress is implicated in the pathogenesis of Alzheimer's disease (AD). A large body of evidence suggests that mitochondrial dysfunction and increased reactive oxygen species occur prior to amyloid-β (Aβ) deposition. Coenzyme Q10 (CoQ10), a component of the mitochondrial electron transport chain, is well characterized as a neuroprotective antioxidant in animal models and human trials of Huntington's disease and Parkinson's disease, and reduces plaque burden in AβPP/PS1 mice. We now show that CoQ10 reduces oxidative stress and amyloid pathology and improves behavioral performance in the Tg19959 mouse model of AD. CoQ10 treatment decreased brain levels of protein carbonyls, a marker of oxidative stress. CoQ10 treatment resulted in decreased plaque area and number in hippocampus and in overlying cortex immunostained with an Aβ42-specific antibody. Brain Aβ42 levels were also decreased by CoQ10 supplementation. Levels of amyloid-β protein precursor (AβPP) β-carboxyterminal fragments were decreased. Importantly, CoQ10-treated mice showed improved cognitive performance during Morris water maze testing. Our results show decreased pathology and improved behavior in transgenic AD mice treated with the naturally occurring antioxidant compound CoQ10. CoQ10 is well tolerated in humans and may be promising for therapeutic trials in AD. [ABSTRACT FROM AUTHOR]

Progranulin haploinsufficiency causes frontotemporal dementia with tau‐negative, ubiq‐uitin‐positive neuronal inclusion pathology. In this study, we showed that progranulin‐deficient mice displayed increased depression‐ and disinhibition‐like behavior, as well as deficits in social recognition from a relatively young age. These mice did not have any deficit in locomotion or exploration. Eighteen‐month‐old progranulin‐deficient mice demonstrated impaired spatial learning and memory in the Morris water maze. In addition to behavioral deficits, progranulin‐deficient mice showed a progressive development of neuropathology from 12 mo of age, including enhanced activation of microglia and astro‐cytes and ubiquitination and cytoplasmic accumulation of phosphorylated TDP‐43. Thus, progranulin deficiency induced FTD‐like behavioral and neuro‐pathological deficits. These mice may serve as an important tool for deciphering underlying mechanisms in frontotemporal dementia.—Yin, F., Du‐mont, M., Banerjee, R., Ma, Y., Li, H., Lin, M. T., Beal, M. F., Nathan, C., Thomas, B., Ding, A. Behavioral deficits and progressive neuropathology in progranulin‐deficient mice: a mouse model of frontotemporal dementia. FASEB J. 24, 4639–4647 (2010). www.fasebj.org [ABSTRACT FROM AUTHOR]

Progranulin haploinsufficiency causes frontotemporal dementia with tau-negative, ubiquitin-positive neuronal inclusion pathology. In this study, we showed that progranulin-deficient mice displayed increased depression- and disinhibition-like behavior, as well as deficits in social recognition from a relatively young age. These mice did not have any deficit in locomotion or exploration. Eighteen-month-old progranulin-deficient mice demonstrated impaired spatial learning and memory in the Morris water maze. In addition to behavioral deficits, progranulin-deficient mice showed a progressive development of neuropathology from 12mo of age, including enhanced activation of microglia and astrocytes and ubiquitination and cytoplasmic accumulation of phosphorylated TDP-43. Thus, progranulin deficiency induced FTD-like behavioral and neuro-pathological deficits. These mice may serve as an important tool for deciphering underlying mechanisms in frontotemporal dementia. [ABSTRACT FROM AUTHOR]

Rod-like structures composed of actin and the actin-binding protein cofilin are found in Alzheimer's disease (AD) patients. However, the mechanisms underlying formation of these structures and their pathological consequences are still largely unknown. We found that microRNAs 103 and 107 repress translation of cofilin, and that reduced levels of miR-103 or miR- 107 are associated with elevated cofilin protein levels and formation of rod-like structures in a transgenic mouse model of AD. These results suggest that microRNAs may play an important role in cytoskeletal pathology in AD. [ABSTRACT FROM AUTHOR]

Accumulation of β-amyloid (Aβ) and loss of synapses are hallmarks of Alzheimer's disease (AD). How synaptic activity relates to A/3 accumulation and loss of synapses is a current topic of major interest. Synaptic activation promotes A/3 secretion, and chronic reduction of synaptic activity reduced Aβ plaques in an AD transgenic mouse model. This suggested beneficial effects of reducing synaptic activity in AD. We now show that reduced synaptic activity causes detrimental effects on synapses and memory despite reducing plaques using two different models of chronic synaptic inhibition: deafferentation of the barrel cortex and administration of benzodiazepine. An interval of prolonged synaptic inhibition exacerbated loss of synaptophysin compared with synaptically more active brain in AD trans- genic but not wild-type mice. Furthermore, an interval ofbenzodiazepine treatment, followed by a washout period, exacerbated memory impairment in AD transgenic mice. Exacerbation of synaptic and behavioral abnormalities occurred in the setting of reduced Aβ plaques but elevated intraneuronal Aβ immunoreactivity. These data support beneficial effects of synaptic activation on Aβ-related synaptic and behavioral impairment in AD. [ABSTRACT FROM AUTHOR]

Background: The mammalian target of rapamycin (mTOR) is an evolutionarily conserved Ser/Thr protein kinase that plays a pivotal role in multiple fundamental biological processes, including synaptic plasticity. We explored the relationship between the mTOR pathway and β-amyloid (Aβ)-induced synaptic dysfunction, which is considered to be critical in the pathogenesis of Alzheimer's disease (AD). Methodology/Principal Findings: We provide evidence that inhibition of mTOR signaling correlates with impairment in synaptic plasticity in hippocampal slices from an AD mouse model and in wild-type slices exposed to exogenous Aβ1-42. Importantly, by up-regulating mTOR signaling, glycogen synthase kinase 3 (GSK3) inhibitors rescued LTP in the AD mouse model, and genetic deletion of FK506-binding protein 12 (FKBP12) prevented Aβ-induced impairment in long-term potentiation (LTP). In addition, confocal microscopy demonstrated co-localization of intraneuronal Aβ42 with mTOR. Conclusions/Significance: These data support the notion that the mTOR pathway modulates Aβ-related synaptic dysfunction in AD. [ABSTRACT FROM AUTHOR]

Oxidative stress and mitochondrial dysfunction are important features present in Alzheimer's disease (AD). They appear early and contribute to disease progression, both in human postmortem AD brains as well as in transgenic AD mouse brains. For this reason, targeting oxidative stress and mitochondria in AD may lead to the development of promising therapeutic strategies. Several exogenous antioxidant compounds have been tested and found beneficial in transgenic AD mice, such as vitamins and spices. However, their efficacy was much more modest in human trials. More recently, new strategies have been elaborated to promote endogenous antioxidant systems. Different pathways involved in oxidative stress response have been identified. Compounds able to upregulate these pathways are being generated and tested in animal models of AD and in human patients. Upregulation of antioxidant gene expression was beneficial in mice, giving hope for future avenues in the treatment of AD and other neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Abstract: A large body of evidence suggests the importance of inflammation and oxidative or nitrosative stress in Alzheimer''s disease (AD) pathogenesis. Inflammatory stimuli upregulate transcription of inducible nitric oxide synthase (iNOS), which can lead to the production of nitric oxide and other reactive nitrogen species. We previously found that genetic deletion of iNOS in mice overexpressing the amyloid precursor protein (APP) and presenilin-1 (PS1) reduced mortality, nitrosative stress, amyloid plaque burden, microgliosis, astrocytosis, and peri-plaque tau phosphorylation. We therefore examined the effects of N6-(1-iminoethyl)-l-lysine (l-NIL), a pharmacological iNOS inhibitor, or d-NIL, its enantiomeric control, in a transgenic mouse model of amyloid deposition. Tg19959 mice carry human APP with two mutations and develop amyloid plaques and memory impairment starting at 3–4 months of age. Mice were given l-NIL or d-NIL in the drinking water from 1 month of age and assessed behaviorally and histopathologically at 8 months of age. We found that l-NIL administration reduced disinhibition in the elevated plus maze, improved spatial memory performance in the Morris water maze, and decreased cortical amyloid deposition as well as microglial activation in 8-month-old Tg19959 mice. These findings are consistent with previous reports demonstrating that iNOS inhibition ameliorates AD pathogenesis. [Copyright &y& Elsevier]

A central question in Alzheimer's disease research is what role synaptic activity plays in the disease process. Synaptic activity has been shown to induce β-amyloid peptide release into the extracellular space, and extracellular β-amyloid has been shown to be toxic to synapses. We now provide evidence that the well established synaptotoxicity of extracellular β-amyloid requires β-secretase processing of amyloid precursor protein. Recent evidence supports an important role for intraneuronal β-amyloid in the pathogenesis of Alzheimer's disease. We show that synaptic activity reduces intraneuronal β-amyloid and protects against β-amyloid-related synaptic alterations. Wedemonstrate that synaptic activity promotes the transport of the amyloid precursor protein to synapses using live cell imaging, and that the protease neprilysin is involved in reduction of intraneuronal β-amyloid with synaptic activity. [ABSTRACT FROM AUTHOR]

In Alzheimer's disease (AD), oxidative stress is present early and contributes to disease pathogenesis. We previously reported that in Tg19959 transgenic AD mice, partial deficiency of the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) exacerbated amyloid pathology. We therefore asked whether MnSOD overexpression would prove beneficial against AD pathogenesis, by studying the offspring of Tg19959 mice crossed with MnSOD-overexpressing mice. At 4 mo of age, there was a 2- to 3-fold increase in MnSOD protein levels in Tg19959MnSOD mice compared to Tg19959 littermates. Tg19959-MnSOD mice also had a 50% increase in catalase protein levels, a 50% decrease in levels of oxidized protein, and a 33% reduction in cortical plaque burden compared to Tg19959 littermates. Spatial memory was impaired and synaptophysin levels were decreased in Tg19959 mice compared to wild-type littermates, but memory and synaptophysin levels were restored to wild-type levels in Tg19959-MnSOD littermates. These benefits occurred without changes in sodium dodecyl sulfate-soluble or formic acid-soluble Aβ pools or Aβ oligomers in Tg19959-MnSOD mice compared to Tg19959 littermates. These data demonstrate that facilitation of the mitochondrial antioxidant response improves resistance to Aβ, slows plaque formation or increases plaque degradation, and markedly attenuates the phenotype in a transgenic AD mouse model. [ABSTRACT FROM AUTHOR]

Oxidative stress is one of the earliest events in the pathogenesis of Alzheimer’s disease (AD) and can markedly exacerbate amyloid pathology. Modulation of antioxidant and anti-inflammatory pathways represents an important approach for AD therapy. Synthetic triterpenoids have been found to facilitate antioxidant response and reduce inflammation in several models. We investigated the effect of the triterpenoid, 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic acid-MethylAmide (CDDO-MA) in Tg19959 mice, which carry the human amyloid precursor protein with two mutations. These mice develop memory impairments and amyloid plaques as early as 2–3 months of age. CDDO-MA was provided with chow (800 mg/kg) from 1 to 4 months of age. CDDO-MA significantly improved spatial memory retention and reduced plaque burden, Aβ42 levels, microgliosis, and oxidative stress in Tg19959 mice. [ABSTRACT FROM AUTHOR]

Immunotherapy against β-amyloid peptide (Aβ) is a leading therapeutic direction for Alzheimer disease (AD), Experimental studies in transgenic mouse models of AD have demonstrated that Aβ immunization reduces Aβ plaque pathology and improves cognitive function. However, the biological mechanisms by which Aβ antibodies reduce amyloid accumulation in the brain remain unclear. We provide evidence that treatment of AD mutant neuroblastoma cells or primary neurons with AD antibodies decreases levels of intracellular Aβ. Antibody-mediated reduction in cellular Aβ appears to require that the anti-body binds to the extracellular Aβ domain of the amyloid precursor protein (APP) and be internalized. In addition, treatment with Aβ antibodies protects against synaptic alterations that occur in APP mutant neurons. [ABSTRACT FROM AUTHOR]

Abstract: Synaptic dysfunction is increasingly viewed as an early manifestation of Alzheimer''s disease (AD), but the cellular mechanism by which β-amyloid (Aβ) may affect synapses remains unclear. Since cultured neurons derived from APP mutant transgenic mice secrete elevated levels of Aβ and parallel the subcellular Aβ accumulation seen in vivo, we asked whether alterations in synapses occur in this setting. We report that cultured Tg2576 APP mutant neurons have selective alterations in pre- and post-synaptic compartments compared to wild-type neurons. Post-synaptic compartments appear fewer in number and smaller, while active pre-synaptic compartments appear fewer in number and enlarged. Among the earliest changes in synaptic composition in APP mutant neurons were reductions in PSD-95, a protein involved in recruiting and anchoring glutamate receptor subunits to the post-synaptic density. In agreement, we observed early reductions in surface expression of glutamate receptor subunit GluR1 in APP mutant neurons. We provide evidence that Aβ is specifically involved in these alterations in synaptic biology, since alterations in PSD-95 and GluR1 are blocked by γ-secretase inhibition, and since exogenous addition of synthetic Aβ to wild-type neurons parallels changes in synaptic PSD-95 and GluR1 observed in APP mutant neurons. [Copyright &y& Elsevier]

A growing body of evidence suggests a relationship between oxidative stress and β-amyloid (Aβ) peptide accumulation, a hallmark in the pathogenesis of Alzheimer's disease (AD). However, a direct causal relationship between oxidative stress and Aβ pathology has not been established in vivo. Therefore, we crossed mice with a knockout of one allele of manganese superoxide dismutase (MnSOD), a critical antioxidant enzyme, with Tg19959 mice, which overexpress a doubly mutated human β-amyloid precursor protein (APP). Partial deficiency of MnSOD, which is well established to cause elevated oxidative stress, significantly increased brain Aβ levels and Aβ plaque burden in Tg19959 mice. These results indicate that oxidative stress can promote the pathogenesis of AD and further support the feasibility of antioxidant approaches for AD therapy. [ABSTRACT FROM AUTHOR]

Multiple lines of evidence implicate β-amyloid (Aβ) in the pathogenesis of Alzheimer's disease (AD), but the mechanisms whereby Aβ is involved remain unclear. Addition of Aβ to the extracellular space can be neurotoxic. Intraneuronal Aβ42 accumulation is also associated with neurodegeneration. We reported previously that in Tg2576 amyloid precursor protein mutant transgenic mice, brain Aβ42 localized by immunoelectron microscopy to, and accumulated with aging in, the outer membranes of multivesicular bodies, especially in neuronal processes and synaptic compartments. We now demonstrate that primary neurons from Tg2576 mice recapitulate the in vivo localization and accumulation of Aβ42 with time in culture. Furthermore, we demonstrate that Aβ42 aggregates into oligomers within endosomal vesicles and along microtubules of neuronal processes, both in Tg2576 neurons with time in culture and in Tg2576 and human AD brain. These Aβ42 oligomer accumulations are associated with pathological alterations within processes and synaptic compartments in Tg2576 mouse and human AD brains. [ABSTRACT FROM AUTHOR]

The pathogenesis of Parkinson''s disease (PD) is largely unknown. Indirect evidence suggests that mutations in mitochondrial DNA (mtDNA) might play a role, but previous studies have not consistently associated any specific mutations with PD. However, these studies have generally been confined to limited areas of the mitochondrial genome. We therefore sequenced the entire mitochondrial genome from substantia nigra of 8 PD and 9 control subjects. Several sequence variants were distributed differently between PD and control subjects, but all were previously reported polymorphisms. Several secondary LHON mutations were found, as well as a number of novel missense mutations, but all were rare and did not differ between PD and control subjects. Finally, PD and control subjects did not differ in the total number of all mutations, nor the total number of missense mutations. Thus, mtDNA involvement in PD, if any, is likely to be complex and should be reconsidered carefully. [Copyright &y& Elsevier]