Search

Immune system dysfunction is increasingly recognized as a significant feature that contributes to Alzheimer's disease (AD) pathogenesis, reflected by alterations in central and peripheral responses leading to detrimental mechanisms that can contribute to the worsening of the disease. The damaging alterations in the peripheral immune system may disrupt the peripheral-central immune crosstalk, implicating the gut microbiota in this complex interaction. The central hypothesis posits that the immune signature inherently harbored in bone marrow (BM) cells can be transferred through allogeneic transplantation, influencing the recipient's immune system and modulating peripheral, gut, and brain immune responses. Employing a genetically modified mouse model to develop AD-type pathology we found that recipient wild-type (WT) mice engrafted with AD-derived BM, recapitulated the peripheral immune inflammatory donor phenotype, associated with a significant acceleration of cognitive deterioration in the absence of any overt change in AD-type amyloid neuropathology. Moreover, transcriptomic and phylogenetic 16S microbiome analysis evidence on these animals revealed a significantly impaired expression of genes associated with synaptic plasticity and neurotransmission in the brain and reduced bacteria diversity, respectively, compared to mice engrafted with WT BM. This investigation sheds light on the pivotal role of the peripheral immune system in the brain-gut-periphery axis and its profound potential to shape the trajectory of AD. In summary, this study advances our understanding of the complex interplay among the peripheral immune system, brain functionality, and the gut microbiome, which collectively influence AD onset and progression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

The present study was designed to further explore the potential cause/effect relationship between the expression of both the N141I presenilin (PS)2 mutant familial Alzheimer's disease (FAD) gene and cyclooxgenase (COX) in respect to the mechanism associated with programmed cell death in Alzheimer's disease (AD). We found that expression of mutant N141I PS2 resulting in apoptotic cell death in H4 neuronal cells coincided with >4-fold induction in the expression of the inducible form of COX-2, but not the constitutive COX-1. Moreover, we found that the expression of the N141I PS2 FAD gene strongly promoted (>2-fold) glycogen synthase kinase (GSK)-3beta activity coincidental with a reduction in the level of beta-catenin translocated from the cytoplasmic to the nuclear compartment. Most interestingly, we found that inhibition of COX-2-mediated generation of prostaglandin (PG)-E2 in H4 neuronal cells with the preferential COX-2 inhibitor nimesulide protects against N141I PS2-mediated apoptotic cell death coincidental with an inhibition of GSK-3beta activity and subsequent normalization of beta-catenin cellular distribution. The clinical relevance of this finding was confirmed by the evidence that COX-2 protein and PG-E2 concentrations were selectively increased >2-fold in the cerebral cortex of subjects harboring the N141I PS2 FAD mutation relative to wild-type PS2 AD cases. This study demonstrates for the first time that COX-2 may be a downstream effector of mutant N141I PS2-mediated apoptotic cell death and that inhibition of COX-2 may neuroprotect in AD through modulation of a GSK-3beta-beta-catenin-mediated response. The study provides support for the potential pharmacogenomic identification of N141I PS2 FAD cases that might preferentially benefit from inhibition of COX-2 during the progression of clinical dementia.

Background: Nonsteroidal anti-inflammatory drugs (NSAID) may be useful in the treatment of AD. Clinical and laboratory experience with nimesulide, an NSAID with preferential cyclooxygenase-2 inhibition, suggests that it may be a good candidate for AD therapy., Methods: This pilot study investigated the clinical feasibility of nimesulide treatment in AD. Forty persons with probable AD, most of whom were taking cholinesterase inhibitors, were enrolled in a randomized, controlled, parallel-group trial designed to assess tolerability and short-term cognitive/behavioral effects of nimesulide. In the initial 12-week double-blind phase, participants were treated with nimesulide 100 mg by mouth twice daily or matching placebo; during the second 12-week phase all participants received active drug. Participants who tolerated the drug well and perceived benefit were invited to continue open-label nimesulide treatment., Results: Short-term therapy with nimesulide, compared with placebo, had no significant effect on total assessment scores of measures of cognition, clinical status, activities of daily living, affect, and behavior. Long-term therapy was well tolerated for periods exceeding 2 years., Conclusion: These findings support the feasibility of nimesulide therapy in AD; assessment of efficacy will require a larger, long-term treatment study.

Alzheimer's disease (AD) is the most common form of dementia, affecting as many as 4 million older persons and results from abnormal changes in the brain that most likely begin long before cognitive impairment and other clinical symptoms become apparent. Thus, efforts aimed at identifying methods of early detection and diagnosis for improving AD care might be the most appropriate strategy to initiate promising new treatments and/or prevention. We used cDNA microarray technology to investigate the sequence of changes in gene expression in brain that may take place during the transition from normal cognitive functioning through the early stages of impairment to frank AD. We examined the expression of approximately 7,000 genes in the brains of cases at the early stage of AD dementia using reference sample cases characterized by normal cognitive status. Genes that are differentially regulated in early AD cases were identified and were categorized into gene clusters based on similarities in biological functions. This analysis revealed that selected biological processes, including protein and amino acid metabolism, cytoskeleton integrity, and fatty acid metabolism, are involved in early phases of AD dementia. Most notable is the observation that selected genes involved in neurotransmitter release are differentially regulated in the brains of cases at high risk for dementia. This evidence supports the feasibility and usefulness of cDNA microarray techniques to study sequential changes of distinctive gene-expression patterns in the brain as a function of the progression of AD dementia. The study suggests new means to dissect and classify stages of AD dementia, or neuropathology, at the molecular level., (Copyright 2001 Wiley-Liss, Inc.)

Background: Prior studies have shown that cyclooxygenase 2 (COX-2), an enzyme involved in inflammatory mechanisms and neuronal activities, is up-regulated in the brain with Alzheimer disease (AD) and may represent a therapeutic target for anti-inflammatory treatments., Objective: To explore COX-2 expression in the brain as a function of clinical progression of early AD., Design and Main Outcome Measures: Using semiquantitative immunocytochemistry, we analyzed COX-2 protein content in the hippocampal formation in 54 postmortem brain specimens from patients with normal or impaired cognitive status., Setting and Patients: Postmortem study of nursing home residents., Results: The immunointensity of COX-2 signal in the CA3 and CA2 but not CA1 subdivisions of the pyramidal layers of the hippocampal formation of the AD brain increased as the disease progressed from questionable to mild clinical dementia as assessed by Clinical Dementia Rating. COX-2 signal was increased in all 3 regions examined among cases characterized by severe dementia., Conclusion: Neuronal COX-2 content in subsets of hippocampal pyramidal neurons may be an indicator of progression of dementia in early AD.

Using a cDNA microarray representing 6794 distinct human genes, we identified candidate genes whose expression is altered in cerebral cortex of cases of early Alzheimer's disease (AD); among these was the synaptic vesicle protein synapsin II, which plays an important role in neurotransmitter release. While other candidate genes are presently under investigation in our lab, in this study we discuss the regulation of synapsin gene expression during the transition from normal cognitive function to early AD. We found a selective decrease in the expression of the synapsin splice variants I-III of the a-type isoform in the entorhinal (EC, BM36) but not visual cortex (VC, BM17) of cases characterized by the earliest clinically detectable stage of AD. In contrast, we found no changes in synapsin splice variant II of the b-type isoform. Alteration of synapsin expression at the earliest clinical stage of AD may suggest novel strategies for improved treatment.

Alzheimer's disease (AD) is the most common form of dementia, affecting as many as four million elderly people. lt results from abnormal changes in the brain that most likely begin long before cognitive impairment and other clinical symptoms become apparent. Little is known about the changes preceding or accompanying initiation of the disease. Using cDNA microarray, we previously reported candidate gene products whose expression is altered in the cerebral cortex of cases at risk for AD dementia. However, it is possible that the cDNA microarray evidence might have underestimated post-transcriptional modifications, and as a result, provided only a partial view of the biological problem of interest. Based on this hypothesis, we initiated a series of parallel high-throughput proteomic studies. We found that, consistent with the cDNA microarray evidence, the expression of proteins involved in synaptic activities was also altered in the brains of early AD cases. These studies support the feasibility and usefulness of high-throughput cDNA and protein microarray techniques to examine the sequential changes of distinctive gene expression patterns in the brain as a function of the progression of AD dementia. Our preliminary results also support the utility of high-throughput proteomic methodologies as a means to identify novel AD biomarkers from cerebral spinal fluid and/or from serum.

We assessed plasma neopterin level as a marker of inflammation in Alzheimer disease (AD). Plasma neopterin levels were higher in 51 patients with AD (9.3 +/- 5.9 ng/mL) than in 38 age-matched control subjects (6.3 +/- 2.6 ng/ml, p = 0.002). There was no correlation between neopterin levels and Mini-Mental State Examination score or duration of disease; there was a weak association between neopterin level and age (r = 0.26, p = 0.02). Although measurement of plasma neopterin levels is not useful for diagnosis, this assay may provide guidance for the development of anti-inflammatory treatment strategies for AD.

Background: Inflammatory cytokines have been linked to Alzheimer disease (AD) neurodegeneration, but little is known about the temporal control of their expression in relationship to clinical measurements of AD dementia progression., Design and Main Outcome Measures: We measured inflammatory cytokine messenger RNA (mRNA) expression in postmortem brain specimens of elderly subjects at different clinical stages of dementia and neuropathological dysfunction., Setting and Patients: Postmortem study of nursing home patients., Results: In brains of cognitively normal control subjects, higher interleukin 6 (IL-6) and transforming growth factor beta1 (TGF-beta1) mRNA expression was observed in the entorhinal cortex and superior temporal gyrus compared with the occipital cortex. Compared with age-matched controls, subjects with severe/terminal dementia, but not subjects at earlier disease stages, had higher IL-6 and TGF-beta1 mRNA expression in the entorhinal cortex (P<.01) and superior temporal gyrus (P<.01). When stratified by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropathological criteria, IL-6 mRNA expression in both the entorhinal cortex (P<.05) and superior temporal gyrus (P<.01) correlated with the level of neurofibrillary tangles but not neuritic plaques. However, in the entorhinal cortex, TGF-beta1 mRNA did not correlate with the level of either neurofibrillary tangles or neuritic plaques. Interestingly, in the superior temporal gyrus, TGF-beta1 mRNA expression negatively correlated with neurofibrillary tangles (P<.01) and showed no relationship to the pathological features of neuritic plaques., Conclusions: The data are consistent with the hypothesis that cytokine expression may differentially contribute to the vulnerability of independent cortical regions during the clinical progression of AD and suggest that an inflammatory cytokine response to the pathological effects of AD does not occur until the late stages of the disease. These findings have implications for the design of anti-inflammatory treatment strategies. Arch Neurol. 2000;57:1153-1160

There is evidence that the complement system, a major component of inflammatory responses, may play an important role in neurodegenerative conditions such as Alzheimer's disease (AD). Work from our lab demonstrated that mice genetically deficient in the complement component C5 are more susceptible to hippocampal excitotoxic lesions (Pasinetti et al., 1996) and that the C5-derived ana;hylatoxin C5a may protect against excitotoxicity in vitro and in vivo (Osaka et al., 1999). Potential mechanisms identified in C5a-mediated neuroprotection include activation of mitogen activated protein (MAP)-kinase (Osaka et al., 1998; Osaka et al., 1999). This novel neuroprotective role of C5a complicates current theories that complement proteins augment beta-amyloid (Abeta) toxicity in AD. In view of the fact that the complement system represents a target for therapeutic interventions in AD, further characterization of the complex role of complement proteins is essential. Towards this aim, we have characterized a transgenic C5a receptor (C5aR) knockout (KO) mouse. Recent studies in the lab using C5aR-KO mice show that disruption of C5aR alters calcium calmodulin kinase (CaM-KII) signal transduction in brain cells. We are presently using C5aR-KO mice to study the role of C5a in caspase mediated apoptotic neuronal death. In this review we will attempt to delineate possible neuroprotective roles for C5a in mechanisms of neurotoxicity pertaining to AD.

Inflammation clearly occurs in pathologically vulnerable regions of the Alzheimer's disease (AD) brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insoluble abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain damaged neurons and neurites and highly insoluble amyloid beta peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation. Because these stimuli are discrete, microlocalized, and present from early preclinical to terminal stages of AD, local upregulation of complement, cytokines, acute phase reactants, and other inflammatory mediators is also discrete, microlocalized, and chronic. Cumulated over many years, direct and bystander damage from AD inflammatory mechanisms is likely to significantly exacerbate the very pathogenic processes that gave rise to it. Thus, animal models and clinical studies, although still in their infancy, strongly suggest that AD inflammation significantly contributes to AD pathogenesis. By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.

Protein kinase C (PKC) has been implicated in the pathophysiology of Alzheimer's disease (AD). The levels of particular isoforms and the activation of PKC are reduced in postmortem brain cortex of AD subjects. Receptors for activated C kinase (RACK) are a family of proteins involved in anchoring activated PKCs to relevant subcellular compartments. Recent evidence has indicated that the impaired activation (translocation) of PKC in the aging brain is associated with a deficit in RACK1, the most well-characterized member of this family. The present study was conducted to determine whether alterations in RACK1 occurred in cortical areas where an impaired translocation of PKC has been demonstrated in AD. Here we report the presence of RACK1 immunoreactivity in human brain frontal cortex for the first time and demonstrate a decrease in RACK1 content in cytosol and membrane extracts in AD when compared with non-AD controls. By comparison, the levels of the RACK1-related PKCbetaII were not modified in the same membrane extracts. These observations add a new perspective in understanding the disease-associated defective PKC signal transduction and indicate that a decrease in an anchoring protein for PKC is an additional determinant of this deficit., (Copyright 1999 Academic Press.)

Cyclooxygenase-2 (COX-2), a key enzyme in prostanoid biosynthesis, may represent an important therapeutic target in Alzheimer's disease (AD). In the present study, we explored the regulation of COX-2 in the hippocampal formation in sporadic AD. Using semiquantitative immunocytochemical techniques, we found that in AD cases (vs. age-matched controls) neurons of the CA1-CA4 subdivisions of the hippocampal pyramidal layer showed elevation of COX-2 signal; COX-2 levels correlated with amyloid plaque density. In contrast, the level of COX-2 immunostaining in the dentate gyrus granule neurons was not elevated in AD. No expression of COX-2 in cells with glial morphology was found in any case examined. In parallel, in vitro studies found that neurons derived from transgenic mice with neuronal overexpression of COX-2 are more susceptible to beta-amyloid (Abeta) toxicity, with potentiation of redox impairment. The results indicate elevated expression of neuronal COX-2 in subregions of the hippocampal formation in AD and that such elevation may potentiate Abeta-mediated oxidative stress., (Copyright 1999 Wiley-Liss, Inc.)

The importance of inflammatory/immune mechanisms in Alzheimer's disease is supported by evidence that the human leukocyte antigen (HLA)-DR genotype influences risk of the disease, with a protective effect associated with the HLA-DR4 allele. We investigated the influence of the HLA-DR4 allele on glial activity, assessed by quantification of glial fibrillary acidic protein (GFAP), in hippocampal tissue from subjects with Alzheimer's disease. The mean GFAP level was significantly higher in Alzheimer's disease hippocampal specimens lacking the HLA-DR4 allele compared to specimens with similar neuropathological findings that were HLA-DR4 positive. Apolipoprotein E genotype had no influence on GFAP levels. These results indicate that HLA-DR4 may exert a protective influence on Alzheimer's disease via modulation of glial activity.

Many epidemiological studies suggest that use of nonsteroidal anti-inflammatory drugs delays or slows the clinical expression of Alzheimer's disease, but the mechanism by which these drugs might affect pathophysiological processes relevant to Alzheimer's disease has been unclear. Non-steroidal anti-inflammatory drugs are presumed to act by inhibiting cyclooxygenase, a key enzyme in the metabolism of membrane-derived arachidonic acid into prostaglandins. In recent years, two distinct isoforms of cyclooxygenase have been characterized, a constitutive form, cyclooxygenase-1, and a mitogen-inducible form, cyclooxygenase-2. Cyclooxygenase-2 has been identified in rodent brain. Excitotoxic lesions cause up-regulation of cyclooxygenase-2 expression coincident with the onset of expression of markers of apoptosis; cyclooxygenase-2 thus represents a possible target of non-steroidal anti-inflammatory drug action in neurodegenerative mechanisms. In the present study, we examined cyclooxygenase-2 gene expression in Alzheimer's disease and control cases. We found up-regulation of cyclooxygenase-2 expression in Alzheimer's disease frontal cortex. Further, we found that synthetic beta-amyloid peptides induced cyclooxygenase-2 expression in SH-SY5Y neuroblastoma cells in vitro, suggesting a mechanism for cyclooxygenase-2 up-regulation in Alzheimer's disease. These findings support the investigation of selective cyclooxygenase-2 inhibitors for the treatment of Alzheimer's disease.

Many epidemiological studies suggest that use of non-steroidal anti-inflammatory drugs (NSAIDs) delay or slow the clinical expression of Alzheimer's disease (AD). While it has been demonstrated that neurodegeneration in AD is accompanied by specific inflammatory mechanisms, including activation of the complement cascade and the accumulation and activation of microglia, the mechanism by which NSAIDs might affect these or other pathophysiological processes relevant to AD has been unclear. New evidence that cyclooxygenase (COX) is involved in neurodegeneration along with the development of selective COX inhibitors has led to renewed interest in the therapeutic potential of NSAIDs in AD.

The inflammatory hypothesis of Alzheimer's disease states that specific inflammatory mechanisms, including the cytokine-driven acute-phase response, complement activation and microglial activation, contribute to neurodegeneration. If the hypothesis is correct, anti-inflammatory treatment aimed at suppression of these mechanisms could slow the rate of disease progression. Towards this goal, a multicentre trial of prednisone in Alzheimer's disease is under way and pilot studies of other anti-inflammatory regimens are being conducted.

We explored the constitutive expression, maturational regulation, and relation to kainic-acid-induced apoptosis of cyclooxygenase (COX)-2 mRNA in rat brain. In adult rats, COX-2 mRNA was expressed primarily in limbic structures. Constitutive COX-2 mRNA expression increased markedly between Postnatal Day 7 (P7) and P14, reaching adult levels by P21. Despite intense KA-induced seizures, no COX-2 mRNA induction was found before P14 in any brain region examined. During response to KA-induced seizures in adult brain, COX-2 mRNA induction paralleled temporally and overlapped anatomically the appearance of cellular morphological features of apoptosis in subsets of cells of the pyramidal neuron layer of the hippocampal formation, amygdaloid complex, and pyriform cortex. While COX-2 mRNA showed KA-induced elevation in the granule cell layer of the dentate gyrus, no detectable morphological features of apoptosis were found in this region. Finally, monotypic culture of rat corticohippocampal neurons confirmed the neuronal expression of COX-2 in vitro and revealed that COX-2 is induced during response to glutamate treatment, leading to neuron death. These studies may provide novel insights into the role of COX-2 and mechanisms of action of nonsteroidal anti-inflammatory drugs in Alzheimer's disease.

This review discusses key findings indicating potential roles of the complement (C)-system in chronic inflammation in Alzheimer's disease (AD) brain. Although there is no means to cure or prevent the disease, recent studies suggest that antiinflammatory drugs may delay the onset of AD dementia. One target of these drugs may be the (C)-system, which is best known for its roles in inflammatory processes in peripheral tissues. However, recent data show C-system expression and regulation in brain cells, and C-system protein deposition in AD plaques. It is still nuclear whether C-system activation contributes to neuropathology in the AD brain, as shown in multiple sclerosis (MS). New clinical studies with antiinflammatory agents are now under general consideration by the Alzheimer's Disease Cooperative Study program. In this review I outline research directions which address possible C-system contributions to neurodegeneration. Finally, I discuss potential pharmacological interventions designed to control segments of classical inflammatory cascades in which the C-system is highly implicated. These aspects are critical to the understanding of C-mediated responses in normal and pathologic brain.

This study examines the relationship between the levels of apolipoprotein E (apoE) and apolipoprotein J (apoJ, also designated as clusterin) as a function of apoE genotype in the hippocampus and cortex of Alzheimer disease (AD) subjects. These two lipophilic proteins which are involved in the maintenance of lipid homeostasis are both synthesized in the brain by astrocytes. Results indicate a reduction of apoE levels in the hippocampus and frontal cortex that is proportional to the apoE4 allele dose. Conversely, apoJ (clusterin) levels were found to increase proportionately to the number of apoE4 allele dose. These results suggest a compensatory induction of apoJ (clusterin) in the brain of apoE4 AD subjects showing low brain levels of apoE.

This study describes evidence in the adult human and rat brain for mRNAs that encode two complement (C) proteins, C1qB and C4. C proteins are important effectors of humoral immunity and inflammation in peripheral tissues but have not been considered as normally present in brain. Previous immunocytochemical studies showed that C proteins are associated with plaques, tangles, and dystrophic neurites in Alzheimer's disease (AD), but their source is unknown. Combined immunocytochemistry and in situ hybridization techniques show C4 mRNA in pyramidal neurons and C1qB mRNA in microglia. Primary rat neuron cultures also show C1qB mRNA. In the cortex from AD brains, there were two- to threefold increases of C1qB mRNA and C4 mRNA, and increased C1qB mRNA prevalence was in part associated with microglia. As a model for AD, we examined entorhinal cortex perforant path transection in the rat brain, which caused rapid increases of C1qB mRNA in the ipsilateral, but not contralateral, hippocampus and entorhinal cortex. The role of brain-derived acute and chronic C induction during AD and experimental lesions can now be considered in relation to functions of C proteins that pertain to cell degeneration and/or cell preservation and synaptic plasticity.

In poly(A) RNA from cerebral cortex obtained postmortem from victims of Alzheimer's disease (AD), an alternatively spliced mRNA for the amyloid precursor protein (APP-695 mRNA) was shown to be decreased by 65%. Another form (APP-751 mRNA) with an additional exon encoding a Kunitz-type (serine) protease inhibitor motif did not change appreciably (less than 30% decrease) in AD cortex. If this twofold increase in the APP-751 mRNA/APP-695 mRNA ratio results in a corresponding increase in the APP-751/APP-695 protein ratio, this would support the hypothesis that impaired proteolysis promotes the accumulation of abnormal proteins in the brain during AD. In the two previously known, major alternatively spliced forms of ca. 3.3 and 3.5 kb, we resolved doublet RNAs for each form that are consistent with sequence data showing multiple polyadenylation sites (J. Kang et al., 1987, Nature (London) 325, 733-736.). Smaller APP-related transcripts were also found (1.1, 1.0, 0.8, and 0.3 kb), some of which are selectively altered in AD.