Pathogenesis Of Sporadic Alzheimer's Disease Research Articles

Toward the development of a sporadic model of Alzheimer's disease: comparing pathologies between humanized APP and the familial J20 mouse models

BackgroundFinding successful therapies for individuals with Alzheimer's disease (AD) remains an ongoing challenge. One contributing factor is that the mouse models commonly used in preclinical research primarily mimic the familial form of AD, whereas the vast majority of human cases are sporadic. Accordingly, for a sporadic mouse model of AD, incorporating the multifactorial aspects of the disease is of utmost importance.MethodsIn the current study, we exposed humanized Aβ knock-in mice (hAβ-KI) to weekly low-dose lipopolysaccharide (LPS) injections until 24 weeks of age and compared the development of AD pathologies to the familial AD mouse model known as the J20 mice.ResultsAt the early time point of 24 weeks, hAβ-KI mice and J20 mice exhibited spatial memory impairments in the Barnes maze. Strikingly, both hAβ-KI mice and J20 mice showed significant loss of dendritic spines when compared to WT controls, despite the absence of Aβ plaques in hAβ-KI mice at 24 weeks of age. Glial cell numbers remained unchanged in hAβ-KI mice compared to WT, and LPS exposure in hAβ-KI mice did not result in memory deficits and failed to exacerbate any other examined AD pathology.ConclusionThe study highlights the potential of hAβ-KI mice as a model for sporadic AD, demonstrating early cognitive deficits and synaptic alterations despite no evidence of Aβ plaque formation. These findings underscore the importance of considering multifactorial influences in sporadic AD pathogenesis and the need for innovative models to advance our understanding and treatment strategies for this complex disease.

Proteomic Analysis Reveals Potential Exosomal Biomarkers in Patients With Sporadic Alzheimer Disease.

Despite substantial progress made in the past decades, the pathogenesis of sporadic Alzheimer disease (sAD) and related biological markers of the disease are still controversially discussed. Cerebrospinal fluid and functional brain imaging markers have been established to support the clinical diagnosis of sAD. Yet, due to the invasiveness of such diagnostics, less burdensome markers have been increasingly investigated in the past years. Among such markers, extracellular vesicles may yield promise in (early) diagnostics and treatment monitoring in sAD. In this pilot study, we collected the blood plasma of 18 patients with sAD and compared the proteome of extracted extracellular vesicles with the proteome of 11 age-matched healthy controls. The resulting proteomes were characterized by Gene Ontology terms and between-group statistics. Ten distinct proteins were found to significantly differ between sAD patients and controls (P<0.05, False Discovery Rate, corrected). These proteins included distinct immunoglobulins, fibronectin, and apolipoproteins. These findings lend further support for exosomal changes in neurodegenerative disorders, and particularly in sAD. Further proteomic research could decisively advance our knowledge of sAD pathophysiology as much as it could foster the development of clinically meaningful biomarkers.

Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis.

Alzheimer's disease (AD) is a debilitating dementia characterized by progressive memory loss and aggregation of amyloid-β (Aβ) protein into amyloid plaques in patient brains. Mutations in presenilin (PS) lead to abnormal generation of Aβ, which is the major cause of familial AD (FAD), and apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) onset. However, whether dysfunction of PS is involved in the pathogenesis of SAD is largely unknown. We found that ApoE secretion was completely abolished in PS-deficient cells and markedly decreased by inhibition of γ-secretase activity. Blockade of γ-secretase activity by a γ-secretase inhibitor, DAPT, decreased ApoE secretion, suggesting an important role of γ-secretase activity in ApoE secretion. Reduced ApoE secretion is also observed in nicastrin-deficient cells with reduced γ-secretase activity. PS deficiency enhanced nuclear translocation of ApoE and binding of ApoE to importin α4, a nuclear transport receptor. Moreover, the expression of PS mutants in PS-deficient cells suppressed the restoration effects on ApoE secretion compared with the expression of wild-type PS. Plasma ApoE levels were lower in FAD patients carrying PS1 mutations compared with normal control subjects. Our findings suggest a novel role of PS contributing to the pathogenesis of SAD by regulating ApoE secretion.SIGNIFICANCE STATEMENT Familial AD (FAD) typically results from mutations in the genes encoding amyloid precursor protein, presenilin 1 (PS1), or PS2. Many PS mutants have been found to exert impaired γ-secretase activity and increased amyloid-β 42 (Aβ42)/Aβ40 ratio, which induce early amyloid deposition and FAD. On the other hand, apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) and contributes to AD pathogenesis because it has reduced Aβ clearance capability compared with ApoE3 and ApoE2. FAD and SAD have long been considered to be caused by these two independent mechanisms; however, for the first time, we demonstrated that PS is essential for ApoE secretion and PS mutants affected ApoE secretion in vitro and in human samples, suggesting a novel mechanism by which PS is also involved in SAD pathogenesis.

Editors' note: Revisiting protein aggregation as pathogenic in sporadic Parkinson and Alzheimer diseases

Despite genetic data from families harboring APP mutations in Alzheimer disease (AD)—or SNCA gene multiplication in familial Parkinson disease (PD)—Dr. Espay et al. emphasized the limited evidence that implicates these protein products in the pathogenesis of sporadic cases of AD/PD. Instead, the authors argued, such proteins may be epiphenomena or could represent the nervous system response to cellular stress. Using established Bradford Hill criteria to determine a cause-and-effect relationship of these proteins and their respective diseases, the authors challenged the “age-old” notion that such proteins play a proximate role in disease pathogenesis. By summarizing the available evidence, the authors concluded “human studies of protein aggregation in AD and PD do not meet a minimum set of Bradford Hill's criteria to support a causal role.” Dr. Nelson respectfully disagrees with the conclusions drawn by the authors, citing evidence that nondemented patients with “preclinical” disease already exhibit abnormal protein deposits in the CNS, whereas demented patients without histopathologic evidence of AD or PD demonstrate pathology consistent with other degenerative conditions. As such, abnormally misfolded and aggregated proteins are more likely to be deleterious rather than protective or reactive. In response, Dr. Espay et al. emphasize the lack of evidence supporting the benefit of antiaggregation therapy (so far) in the treatment of patients with preclinical disease. Targeting these proteins, or preventing their aggregation, may fail to address the occult, proximate causes underlying these conditions. Although the jury may still be out regarding this chicken or the egg dilemma, it stands to reason that we should consider alternative hypotheses in the pathogenesis of sporadic AD or PD, if only to avoid perpetuating confirmation bias. Despite genetic data from families harboring APP mutations in Alzheimer disease (AD)—or SNCA gene multiplication in familial Parkinson disease (PD)—Dr. Espay et al. emphasized the limited evidence that implicates these protein products in the pathogenesis of sporadic cases of AD/PD. Instead, the authors argued, such proteins may be epiphenomena or could represent the nervous system response to cellular stress. Using established Bradford Hill criteria to determine a cause-and-effect relationship of these proteins and their respective diseases, the authors challenged the “age-old” notion that such proteins play a proximate role in disease pathogenesis. By summarizing the available evidence, the authors concluded “human studies of protein aggregation in AD and PD do not meet a minimum set of Bradford Hill's criteria to support a causal role.” Dr. Nelson respectfully disagrees with the conclusions drawn by the authors, citing evidence that nondemented patients with “preclinical” disease already exhibit abnormal protein deposits in the CNS, whereas demented patients without histopathologic evidence of AD or PD demonstrate pathology consistent with other degenerative conditions. As such, abnormally misfolded and aggregated proteins are more likely to be deleterious rather than protective or reactive. In response, Dr. Espay et al. emphasize the lack of evidence supporting the benefit of antiaggregation therapy (so far) in the treatment of patients with preclinical disease. Targeting these proteins, or preventing their aggregation, may fail to address the occult, proximate causes underlying these conditions. Although the jury may still be out regarding this chicken or the egg dilemma, it stands to reason that we should consider alternative hypotheses in the pathogenesis of sporadic AD or PD, if only to avoid perpetuating confirmation bias.

ESSENTIAL INVOLVEMENT OF OLIGODENDROGLIAS IN THE PATHOGENESIS OF SPORADIC ALZHEIMER’S DISEASE

Sporadic Alzheimer's disease (SAD) is the biggest target of drug development, although its pathological process still has been elusive. It must be promoted (or protected) by genetic factors, however, the research has long been dominated by a single direct causality called the amyloid b (Ab) hypothesis, rejecting alternative ones. We investigated roles of oligodendrocyte (OL) lineage cells in the pathogenesis of SAD by establishing a method to purify and culture adult OL progenitor cells (aOPCs) from the rat hippocampus and by investigating postmortem human brains. We found novel aOPCs expressing plexin-B3 as Ab secreting cells. A small population of plexin-B3+ aOPCs was persistently cultured in fibroblast growth factor 2 (FGF2) and FGF2 withdrawal increased plexin-B3+ but decreased NG2+ aOPCs, with cored plaque-like morphological changes and increased Ab1–42 secretion greater than that of cultured fetal neurons. They express massive amounts of APP, the components of gamma-secretase, and the receptors of apolipoprotein E. In vivo, plexin-B3+ aOPCs distributed throughout the adult brain and spreading depolarization, a common mechanism of cortical injuries, induced unique delayed cortical gliosis of plexin-B3+ aOPCs whose distribution resembles to that of cored senile plaques. In human AD brains, cortical senile plaques were mostly immunostained with plexin-B3 antibodies. These findings suggest that plexin-B3+ aOPCs play essential roles in the pathogenesis of SAD as Ab secreting cells. Fine control of a SAD-type demyelination in the aged cortex would be a novel, promising and unexplored therapeutic target for SAD.

Decreased gene expression of CD2AP in Chinese patients with sporadic Alzheimer's disease

Many sporadic Alzheimer's disease (SAD) risk genes have been identified in the last decades, but most of them have not been consistently accepted. Here, we sought to identify SAD-associated genes and their potential mechanisms involved in SAD pathogenesis. A 2-stage design was employed. In stage 1, 95 variants in 75 genes that were previously reported as SAD-risk genes in Caucasian populations were evaluated in 1857 subjects (422 SAD patients and 1435 controls). In stage 2, a subset of promising variants found in stage 1 were further evaluated in an independent cohort of 1001 subjects (254 SAD and 747 controls). Variants in CD2AP were significantly associated with SAD risk in our subjects. Furthermore, CD2AP gene expression in peripheral blood lymphocytes (PBL) from 209 SAD patients and 213 controls was determined. CD2AP gene expression in PBL was significantly decreased in patients with SAD as compared with controls. Our study suggests that CD2AP is an SAD-risk gene in Chinese Han population and CD2AP gene expression is decreased in the PBL of patients with SAD, indicating its possible systemic involvement in SAD.

A Novel Genetic Screen Identifies Modifiers of Age-Dependent Amyloid β Toxicity in the Drosophila Brain

The accumulation of amyloid β peptide (Aβ) in the brain of Alzheimer’s disease (AD) patients begins many years before clinical onset. Such process has been proposed to be pathogenic through the toxicity of Aβ soluble oligomers leading to synaptic dysfunction, phospho-tau aggregation and neuronal loss. Yet, a massive accumulation of Aβ can be found in approximately 30% of aged individuals with preserved cognitive function. Therefore, within the frame of the “amyloid hypothesis”, compensatory mechanisms and/or additional neurotoxic or protective factors need to be considered and investigated. Here we describe a modifier genetic screen in Drosophila designed to identify genes that modulate toxicity of Aβ42 in the CNS. The expression of Aβ42 led to its accumulation in the brain and a moderate impairment of negative geotaxis at 18 days post-eclosion (d.p.e) as compared with genetic or parental controls. These flies were mated with a collection of lines carrying chromosomal deletions and negative geotaxis was assessed at 5 and 18 d.p.e. Our screen is the first to take into account all of the following features, relevant to sporadic AD: (1) pan-neuronal expression of wild-type Aβ42; (2) a quantifiable complex behavior; (3) Aβ neurotoxicity associated with progressive accumulation of the peptide; and (4) improvement or worsening of climbing ability only evident in aged animals. One hundred and ninety-nine deficiency (Df) lines accounting for ~6300 genes were analyzed. Six lines, including the deletion of 52 Drosophila genes with human orthologs, significantly modified Aβ42 neurotoxicity in 18-day-old flies. So far, we have validated CG11796 and identified CG17249 as a strong candidate (whose human orthologs are HPD and PRCC, respectively) by using RNAi or mutant hemizygous lines. PRCC encodes proline-rich protein PRCC (ppPRCC) of unknown function associated with papillary renal cell carcinoma. HPD encodes 4-hydroxyphenylpyruvate dioxygenase (HPPD), a key enzyme in tyrosine degradation whose Df causes autosomal recessive Tyrosinemia type 3, characterized by mental retardation. Interestingly, lines with a partial Df of HPD ortholog showed increased intraneuronal accumulation of Aβ42 that coincided with geotaxis impairment. These previously undetected modifiers of Aβ42 neurotoxicity in Drosophila warrant further study to validate their possible role and significance in the pathogenesis of sporadic AD.

Molecular Basis of Familial and Sporadic Alzheimer's Disease.

Alzheimer's disease (AD) is a multifactorial disease with genetic (70%) and environmental (30%) causes. Among the genetic factors are genes associated with a family history of the disease (familial AD, FAD) and sporadic AD (SAD). The genes: APP (amyloid precursor protein), PSEN1 (Presenilin 1) and PSEN2 (Presenilin 2) are responsible for the presence of FAD. The APOE gene is responsible for the sporadic form of the disease. Other molecular factors related to the immunological cause (TREM2) of the disease are a disorder of the lipid (ABCA1, ABCA7) or biothiol (MTHFD1) metabolism and of the transport of metabolites (BIN1). Currently, it is believed that APOE is a risk factor for both SAD and late-onset FAD. The pathomechanism of AD is most commonly explained as based on the amyloid cascade theory. This theory is related to the FAD, although there are reports indicating the probability of its occurrence in the SAD. It seems that the excessive deposition of β-amyloid (Aβ) peptides and intracellular neurofibrillary tangles of tau protein hyperphosphorylated forms contribute to the damage of both DNA and RNA. Furthermore, it is believed that RNA-interference can affect both the level of pathological proteins (Aβ, tau protein) and the onset and progress of AD. It seems that a complete understanding of both FAD and SAD pathogenesis may contribute to the search for earlier clinical diagnosis and to an understanding of later occurrence of the disease, which may help modify its course and affect more effective therapy of this incurable neurological disease.

Somatic signature of brain-specific single nucleotide variations in sporadic Alzheimer's disease.

Although genome-wide association studies have shown that genetic factors increase the risk of suffering late-onset, sporadic Alzheimer's disease (SAD), the molecular mechanisms responsible remain largely unknown. The aim of the study was to investigate the presence of somatic, brain-specific single nucleotide variations (SNV) in the hippocampus of SAD samples. By using bioinformatic tools, we compared whole exome sequences in paired blood and hippocampal genomic DNAs from 17 SAD patients and from 2 controls and 2 vascular dementia patients. We found a remarkable number of SNVs in SAD brains (~575 per patient) that were not detected in blood. Loci with hippocampus-specific (hs)-SNVs were common to several patients, with 38 genes being present in 6 or more patients out of the 17. While some of these SNVs were in genes previously related to SAD (e.g., CSMD1, LRP2), most hs-SNVs occurred in loci previously unrelated to SAD. The most frequent genes with hs-SNVs were associated with neurotransmission, DNA metabolism, neuronal transport, and muscular function. Interestingly, 19 recurrent hs-SNVs were common to 3 SAD patients. Repetitive loci or hs-SNVs were underrepresented in the hippocampus of control or vascular dementia donors, or in the cerebellum of SAD patients. Our data suggest that adult blood and brain have different DNA genomic variations, and that somatic genetic mosaicism and brain-specific genome reshaping may contribute to SAD pathogenesis and cognitive differences between individuals.

Geniposide Ameliorates Learning Memory Deficits, Reduces Tau Phosphorylation and Decreases Apoptosis via GSK3β Pathway in Streptozotocin‐Induced Alzheimer Rat Model

Intracerebral-ventricular (ICV) injection of streptozotocin (STZ) induces an insulin-resistant brain state that may underlie the neural pathogenesis of sporadic Alzheimer disease (AD). Our previous work showed that prior ICV treatment of glucagon-like peptide-1 (GLP-1) could prevent STZ-induced learning memory impairment and tau hyperphosphorylation in the rat brain. The Chinese herbal medicine geniposide is known to relieve symptoms of type 2 diabetes. Because geniposide is thought to act as a GLP-1 receptor agonist, we investigated the potential therapeutic effect of geniposide on STZ-induced AD model in rats. Our result showed that a single injection of geniposide (50 μM, 10 μL) to the lateral ventricle prevented STZ-induced spatial learning deficit by about 40% and reduced tau phosphorylation by about 30% with Morris water maze test and quantitative immunohistochemical analysis, respectively. It has been known that tau protein can be phosphorylated by glycogen synthase kinase-3 (GSK3) and STZ can increase the activity of GSK3β. Our result with Western blot analysis showed that central administration of geniposide resulted in an elevated expression of GSK3β(pS-9) but suppressed GSK3β(pY-216) indicating that geniposide reduced STZ-induced GSK3β hyperactivity. In addition, ultrastructure analysis showed that geniposide averted STZ-induced neural pathology, including paired helical filament (PHF)-like structures, accumulation of vesicles in synaptic terminal, abnormalities of endoplasmic reticulum (ER) and early stage of apoptosis. In summary, our study suggests that the water soluble and orally active monomer of Chinese herbal medicine geniposide may serve as a novel therapeutic agent for the treatment of sporadic AD.

Altered Cholesterol Intracellular Trafficking and the Development of Pathological Hallmarks of Sporadic AD.

Compared to the rare familial early onset Alzheimer's disease (AD) that results from gene mutations in AbPP and presenilin-1, the pathogenesis of sporadic AD is much more complex and is believed to result from complex interactions between nutritional, environmental, epigenetic and genetic factors. Among those factors, the presence APOE4 is still the single strongest genetic risk factor for sporadic AD. However, the exact underlying mechanism whereby apoE4 contributes to the pathogenesis of sporadic AD remains unclear. Here, we discuss how altered cholesterol intracellular trafficking as a result of apoE4 might contribute to the development of pathological hallmarks of AD including brain deposition of amyloid beta (Ab), neurofibrillary tangles, and synaptic dysfunction.

High-sugar diets, type 2 diabetes and Alzheimerʼs disease

Recent findings suggest that high-sugar diets can lead to cognitive impairment predisposing to neurodegenerative disorders such as Alzheimer's disease. This article discusses metabolic derangements induced by high-fructose/sucrose diets and presents evidence for the involvement of insulin resistance in sporadic Alzheimer's disease pathogenesis. There has been much concern regarding the role of dietary sugars (fructose/sucrose) in the development of type 2 diabetes (T2D). Accumulating evidence has also demonstrated a connection between T2D and Alzheimer's disease. The risk for developing T2D and Alzheimer's disease increases exponentially with age and having T2D increases the risk of developing Alzheimer's disease. The incidence of T2D increased dramatically over the last decades mainly due to Western lifestyle factors such as lack of exercise and high calorie diets. In fact, high-sugar diets are thought to promote weight gain and insulin resistance predisposing to T2D. To aggravate this scenario, it has been consistently shown that T2D is a risk factor for Alzheimer's disease and both disorders share similar demographic profiles, risk factors, and clinical and biochemical features (e.g. insulin resistance). Therefore, dietary changes can significantly reduce the risk of T2D and Alzheimer's disease and thereby increase the quality of life and improve longevity.

Mitochondrial DNA deletions cause the biochemical defect observed in Alzheimer's disease

Alzheimer's disease (AD) is the most common form of dementia, increasing in prevalence with age. Most patients who develop AD have an unknown cause, but characteristic neuropathological features include the deposition of extracellular amyloid beta and of intraneuronal hyperphosphorylated tau protein. Researchers have previously implicated mitochondrial dysfunction in AD. We previously showed an increase in neurons displaying a mitochondrial biochemical defect—cytochrome-c oxidase (COX) deficiency—in the hippocampus in patients with sporadic AD compared with age-matched controls. COX deficiency is well described as a marker of mitochondrial (mt) DNA dysfunction. This present study analyzed the mtDNA in single neurons from both COX normal and COX-deficient cells. Analysis of the mtDNA revealed that COX deficiency is caused by high levels of mtDNA deletions which accumulate with age. Future research is needed to clarify the role mtDNA deletions have in normal aging and investigate the relationship between mtDNA deletions and the pathogenesis of sporadic AD.

Alternative processing of γ‐secretase substrates in common forms of mild cognitive impairment and alzheimer's disease: Evidence for γ‐secretase dysfunction

The most common pathogenesis for familial Alzheimer's disease (FAD) involves misprocessing (or alternative processing) of the amyloid precursor protein (APP) by γ-secretase due to mutations of the presenilin 1 (PS1) gene. This misprocessing/alternative processing leads to an increase in the ratio of the level of a minor γ-secretase reaction product (Aβ42) to that of the major reaction product (Aβ40). Although no PS1 mutations are present, altered Aβ42/40 ratios are also observed in sporadic Alzheimer's disease (SAD), and these altered ratios apparently reflect deposition of Aβ42 as amyloid. Using immunoprecipitation-mass spectrometry with quantitative accuracy, we analyzed in the cerebrospinal fluid (CSF) of various clinical populations the peptide products generated by processing of not only APP but also an unrelated protein, alcadein (Alc). Alc undergoes metabolism by the identical APP α-secretases and γ-secretases, yielding a fragment that we have named p3-Alc(α) because of the parallel genesis of p3-Alc(α) peptides and the p3 fragment of APP. As with Aβ, both major and minor p3-Alc(α) s are generated. We studied the alternative processing of p3-Alc(α) in various clinical populations. We previously reported that changes in the Aβ42/40 ratio showed covariance in a linear relationship with the levels of p3-Alc(α) [minor/major] ratio in media conditioned by cells expressing FAD-linked PS1 mutants. Here we studied the speciation of p3-Alc(α) in the CSF from 3 groups of human subjects (n = 158): elderly nondemented control subjects; mild cognitive impairment (MCI) subjects with a clinical dementia rating (CDR) of 0.5; SAD subjects with CDR of 1.0; and other neurological disease (OND) control subjects. The CSF minor p3-Alc(α) variant, p3-Alc(α) 38, was elevated (p < 0.05) in MCI subjects or SAD subjects, depending upon whether the data were pooled and analyzed as a single cohort or analyzed individually as 3 separate cohorts. These results suggest that some SAD may involve alternative processing of multiple γ-secretase substrates, raising the possibility that the molecular pathogenesis of SAD might involve γ-secretase dysfunction.

Dual Role of α-Secretase Cleavage in the Regulation of γ-Secretase Activity for Amyloid Production

Processing of the amyloid precursor protein (APP) by β- and γ-secretases generates pathogenic β-amyloid (Aβ) peptides associated with Alzheimer disease (AD), whereas cleavage of APP by α-secretases precludes Aβ formation. Little is known about the role of α-secretase cleavage in γ-secretase regulation. Here, we show that α-secretase-cleaved APP C-terminal product (αCTF) functions as an inhibitor of γ-secretase. We demonstrate that the substrate inhibitory domain (ASID) within αCTF, which is bisected by the α-secretase cleavage site, contributes to this negative regulation because deleting or masking this domain turns αCTF into a better substrate for γ-secretase. Moreover, α-secretase cleavage can potentiate the inhibitory effect of ASID. Inhibition of γ-secretase activity by αCTF is observed in both in vitro and cellular systems. This work reveals an unforeseen role for α-secretase in generating an endogenous γ-secretase inhibitor that down-regulates the production of Aβ. Deregulation of this feedback mechanism may contribute to the pathogenesis of AD.

Nerve growth factor attenuates oxidant‐induced β‐amyloid neurotoxicity in sporadic Alzheimer’s disease cybrids

Although mitochondrial dysfunction has been linked to Alzheimer's disease (AD), it is not fully understood how this dysfunction may induce neuronal death. In this study, we show that transmitochondrial hybrid cells (cybrids) expressing mitochondrial genes from patients with sporadic AD (SAD) have substantial alterations in basal upstream tyrosine kinase signaling and downstream serine-threonine kinase signaling that are mediated by intracellular free radicals. This is associated with reduced tropomyocin receptor kinase (TrkA) and p75 neurotrophin receptor receptor expression that profoundly alters nerve growth factor signaling, increases generation of Aβ and decreases viability. Many of these observed effects in SAD cybrids would be predicted to increase risk of premature neuronal death and reduce resistance to stressors and add further support for the pathogenic role of mtDNA expression in the pathogenesis of SAD.

AGEs/RAGE complex upregulates BACE1 via NF-κB pathway activation

Although the pathogenesis of sporadic Alzheimer disease (AD) is not clearly understood, it is likely dependent on several age-related factors. Diabetes is a risk factor for AD, and multiple mechanisms connecting the 2 diseases have been proposed. Hyperglycemia enhances the formation of advanced glycation end products (AGEs) that result from the auto-oxidation of glucose and fructose. The interaction of AGEs with their receptor, named RAGE, elicits the formation of reactive oxygen species that are also believed to be an early event in AD pathology. To investigate a functional link between the disorders diabetes and AD, the effect of 2 AGEs, pentosidine and glyceraldehydes-derived pyridinium (GLAP), was studied on BACE1 expression both in vivo, in streptozotocin treated rats, and in vitro in differentiated neuroblastoma cells. We showed that pentosidine and GLAP were able to upregulate BACE1 expression through their binding with RAGE and the consequent activation of NF-κB. In addition, both pentosidine and GLAP were found to be increased in the brain in sporadic AD patients. Our findings demonstrate that activation of the AGEs/RAGE axis, by upregulating the key enzyme for amyloid-β production, provides a pathologic link between diabetes mellitus and AD.

High Striatal Amyloid β-Peptide Deposition Across Different Autosomal Alzheimer Disease Mutation Types

Supported by compelling genetic data regarding early-onset familial Alzheimer disease (AD), the amyloid beta-peptide (Abeta)-centric theory holds that Abeta is involved in the pathogenesis of sporadic AD. Mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes lead to increased Abeta levels before symptoms arise. To evaluate the pattern of Pittsburgh Compound B (PiB) retention in subjects with different autosomal dominant mutations associated with familial AD vs that in healthy age-matched control subjects and subjects with probable sporadic AD, to correlate Abeta burden as measured by PiB with available clinical and cognitive data, and to compare the regional brain patterns of PiB retention and fluorodeoxyglucose F 18 (FDG) uptake. Correlation analysis of positron emission tomography (PET) imaging studies. Academic research. Seven PSEN1 mutation carriers and 1 APP mutation carrier underwent PiB and FDG PET imaging. Amyloid beta-peptide burden and FDG uptake were established using standardized uptake values normalized to pons. Primary outcomes were PET results, which were compared with those of a well-characterized cohort of 30 healthy control subjects and 30 subjects with probable sporadic AD. All mutation carriers had high PiB retention in the striatum, with some also having cortical PiB retention in ventrofrontal and posterior cingulate/precuneus areas. The striatal pattern of PiB retention was similar in the PSEN1 and APP mutation carriers. Neither striatal nor cortical Abeta burden was related to cognitive status. Consistent with previous studies, the pattern of Abeta deposition in familial AD differs from that in sporadic AD, with higher striatal and somewhat lower cortical PiB retention in familial AD. The pattern and degree of Abeta deposition were not associated with mutation type nor cognitive status.

Association between somatostatin gene polymorphisms and sporadic Alzheimer's disease in Chinese population

Recent evidence has suggested that down-regulation of somatostatin (SST) expression in the human brain during early stages of aging leads to an elevation in the steady-state levels of Aβ and therefore may be involved in Alzheimer's disease (AD) progression. We hypothesized that alterations in the SST gene might alter its expression or function and also play a role in the pathogenesis of sporadic AD (SAD). First, we sequenced the entire SST gene in 25 randomly selected controls and 25 SAD patients and then screened for C/T polymorphisms (rs4988514) in the 3′ un-translated region. We genotyped rs4988514 polymorphisms as well as apolipoprotein ɛ4 (APOE ɛ4) status in 309 SAD patients and 276 normal controls with restriction fragment length polymorphism (RFLP) analysis. Results showed that the C allele of the rs4988514 polymorphism had an increased incidence in the SAD group compared to the control group (p=0.042). In subjects with the APOE ɛ4 allele, the presence of both the CC genotype and the C allele of this polymorphism were elevated in the SAD group compared to the control group (genotype p=0.027, allele p=0.011). In the whole study group, the age, sex, and APOE ɛ4 adjusted OR for the risk of AD in C allele carriers was 1.313 (95%CI=1.068–2.234, p=0.027) whereas within only APOE ɛ4 allele carriers, the adjusted OR increased to 2.734 (95%CI=1.236–5.862, p=0.012). Our results supported the notion that the C allele of the rs4988514 polymorphism may increase the risk for AD in the Chinese population and possibly have additive effect with the APOE ɛ4 allele.

A POSSIBLE ROLE OF ATRIAL FIBRILLATION AS A RISK FACTOR FOR DEMENTIA

Atrial fibrillation (AF), which is a very common disease among the elderly, is already well known as a risk factor for arterial thromboembolism and stroke. The attention of medical research is now focused on establishing a possible role of AF in the development of cognitive impairment in order to include this arrhythmia among risk factors for dementia. The aim of this work was to investigate the relationship between AF and various types of dementia, such as vascular dementia (VaD), Alzheimer's disease (AD) and mixed dementia (MD). The study consisted of 71 VaD, AD or MD patients, 31 males and 40 females. The sample has been divided in 2 groups according to the sex, and these two groups have been analyzed separately. In females, a statistically significant association was found between mini mental state examination (MMSE) and clinical dementia rating (CDR) scores and AF occurrence (r = −0.32; p < 0.05; r = 0.33; p < 0.05). On the contrary, no significant linear correlation was found between AF and a lower activities if daily living (ADL) and instrumental activities if daily living (IADL) scores. In males, AF/MMSE, AF/CDR, AF/ADL and AF/IADL variables have not been found to be linearly related to each other. Unexpectedly, AF turned to be associated to AD more often than to VAD, becoming a possible risk factor for this neurodegenerative disease. Our results are supported by many studies in literature attributing a basic role of brain hypoperfusion in sporadic AD patho-genesis. More and more scientific data suggest that the already well known risk factors for AD could be considered just the top of an iceberg, providing powerful arguments for impaired cerebral perfusion as the primary trigger in the development of this disease. Moreover, the mildly favorable treatment response in patients with AD to therapy that improves cerebral blood flow is a consistent finding; the same cannot be said of antiamyloid treatments. This opens new possibilities to find an effective way to treat this dramatic pathology.