Appearance Of Senile Plaques Research Articles

Hypothesis review: Alzheimer's overture guidelines.

National Institute on Aging-Alzheimer's Association definition and classification of sporadic Alzheimer's disease (sAD) is based on the assumption that β-amyloid drives the pathogenesis of sAD, and therefore, β-amyloid pathology is the sine-qua-non condition for the diagnosis of sAD. The neuropathological diagnosis is based on the concurrence of senile plaques (SPs) and neurofibrillary tangles (NFTs) designated as Alzheimer's disease neuropathological changes. However, NFTs develop in the brain decades before the appearance of SPs, and their distribution does not parallel the distribution of SPs. Moreover, NFTs are found in about 85% of individuals at age 65 and around 97% at age 80. SPs occur in 30% at age 65 and 50%-60% at age 80. More than 70 genetic risk factors have been identified in sAD; the encoded proteins modulate cell membranes, synapses, lipid metabolism, and neuroinflammation. Alzheimer's disease (AD) overture provides a new concept and definition of brain aging and sAD for further discussion. AD overture proposes that sAD is: (i) a multifactorial and progressive neurodegenerative biological process, (ii) characterized by the early appearance of 3R + 4Rtau NFTs, (iii) later deposition of β-amyloid and SPs, (iv) with particular non-overlapped regional distribution of NFTs and SPs, (v) preceded by or occurring in parallel with molecular changes affecting cell membranes, cytoskeleton, synapses, lipid and protein metabolism, energy metabolism, neuroinflammation, cell cycle, astrocytes, microglia, and blood vessels; (vi) accompanied by progressive neuron loss and brain atrophy, (vii) prevalent in human brain aging, and (viii) manifested as pre-clinical AD, and progressing not universally to mild cognitive impairment due to AD, and mild, moderate, and severe AD dementia.

Probable Reasons for Neuron Copper Deficiency in the Brain of Patients with Alzheimer’s Disease: The Complex Role of Amyloid

Alzheimer’s disease is a progressive neurodegenerative disorder that eventually leads the affected patients to die. The appearance of senile plaques in the brains of Alzheimer’s patients is known as a main symptom of this disease. The plaques consist of different components, and according to numerous reports, their main components include beta-amyloid peptide and transition metals such as copper. In this disease, metal dyshomeostasis leads the number of copper ions to simultaneously increase in the plaques and decrease in neurons. Copper ions are essential for proper brain functioning, and one of the possible mechanisms of neuronal death in Alzheimer’s disease is the copper depletion of neurons. However, the reason for the copper depletion is as yet unknown. Based on the available evidence, we suggest two possible reasons: the first is copper released from neurons (along with beta-amyloid peptides), which is deposited outside the neurons, and the second is the uptake of copper ions by activated microglia.

Contribution of Alzheimer's disease risk genes in the maintenance of endolysosomal transport regulation.

Alzheimer's disease (AD) is the most common form of dementia of which the incidence increases with age. AD has a strong genetic component, for which further study is essential to identify pathways that can be targeted therapeutically, as no cure is available yet. While most studies have focused over the years on the early onset risk factors (i.e. APP, PSEN1 and PSEN2), those represent only a minor fraction of all cases. GWAS studies have identified ≈30 late-onset AD (LOAD) susceptibility loci that, when functionally clustered, are directly or indirectly linked to cellular trafficking routes and functioning. These include genes linked to cholesterol metabolism, endocytic transport regulation and lysosomal processes. The genetic findings concur with the appearance of endolysosomal abnormalities at preclinical stages, before the appearance of senile plaques and tangles. Using a CRISPR-Cas9 based approach, knock-out (KO) of various risk factors from early (PSEN1) or late (PICALM, PLD3) onset risk factors were realized in fibroblasts and neuronal SH-SY5Y cells. Analysis of the endolysosomal pathway and lysosomal functions were carried out using biochemical assays, lipidomic analysis of isolated organelles, confocal imaging as well as electron microscopy. Both the deficiency of presenilins and late risk factors led to endolysosomal dysfunctions, as characterized by an enlargement of late endosomes/lysosomes that accumulate diverse types of lipids such as cholesterol or glycerophospholipids. Further focusing on PSENs, their depletion led to a delay in the endosomal maturation, resulting in an accumulation of endosomal cargoes and adapters such as the retromer subunit VPS35. Re-expression of either catalytic or inactive PSEN1 was sufficient to correct these aberrant accumulations. Whereas the endolysosomal abnormalities could be connected to the accumulation of APP-CTFs, the nature of γ-secretase-independent contribution remains enigmatic. Activation of recycling significantly alleviated endolysosomal defects observed in PSENdKO cells. Altogether, our results underscore that different upstream mechanisms could lead to similar endolysosomal dysfunctions. Our observations are also shedding light on the potential of modulating/restoring endosomal recycling regulation as a strategy to alleviate observed early endolysosomal dysfunctions at preclinical stages of AD pathogenesis.

Exploitation of Marine Molecules to Manage Alzheimer's Disease.

Neurodegenerative diseases are sociosanitary challenges of today, as a result of increased average life expectancy, with Alzheimer’s disease being one of the most prevalent. This pathology is characterized by brain impairment linked to a neurodegenerative process culminating in cognitive decline and behavioral disorders. Though the etiology of this pathology is still unknown, it is usually associated with the appearance of senile plaques and neurofibrillary tangles. The most used prophylaxis relies on anticholinesterase drugs and NMDA receptor antagonists, whose main action is to relieve symptoms and not to treat or prevent the disease. Currently, the scientific community is gathering efforts to disclose new natural compounds effective against Alzheimer’s disease and other neurodegenerative pathologies. Marine natural products have been shown to be promising candidates, and some have been proven to exert a high neuroprotection effect, constituting a large reservoir of potential drugs and nutraceutical agents. The present article attempts to describe the processes of extraction and isolation of bioactive compounds derived from sponges, algae, marine bacteria, invertebrates, crustaceans, and tunicates as drug candidates against AD, with a focus on the success of pharmacological activity in the process of finding new and effective drug compounds.

Contribution of Alzheimer’s disease risk genes in the maintenance of endolysosomal transport regulation

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of dementia of which the incidence increases with age. No cures are available yet, urging to explore new strategies for the identification of pathways that can be targeted therapeutically. Research in AD has been majorly driven by studying familial AD (FAD)‐associated mutations in the APP and PSEN genes, albeit they represent only a minor fraction of all cases. GWAS studies have identified ≈30 late‐onset AD (LOAD) susceptibility loci that, when functionally clustered, are directly or indirectly linked to cellular trafficking routes and functioning. These include genes linked to cholesterol metabolism (e.g. APOE4, ABCA7, INPP5D), endocytic transport regulation (e.g. BIN1, CD2AP, PICALM, SORL1) and lysosomal processes (e.g. GRN, PLD3). The genetic findings concur with the appearance of endolysosomal abnormalities at preclinical stages, before the appearance of senile plaques and tangles.MethodTo investigate the role of LOAD risk factors involved endosomal transport regulation, we generated knock‐out (KO), and their corresponding rescued cell lines for several proteins including PSENs, PICALM and PLD3 and this in fibroblasts and neuronal SHS5Y5Y cells. These are now subjected to a comparative analysis of the endolysosomal pathway and lysosomal function.ResultPSENdKO cells present with enlarged late endosomes/lysosomes that (i) display an increased co‐localization with early endosomal markers, (ii) accumulate various lipids as shown by lipidome profiling of isolated organelles, and (iii) accumulate various cargoes and adaptors such as the retromer subunit VPS35. These aberrant accumulations could be corrected by the re‐expression of catalytic active and inactive human PSEN1, indicating that a γ‐secretase‐independent role of PSEN1 is partially connected to recycling. Interestingly, activation of recycling could significantly alleviate endolysosomal defects observed in PSEN KO cells. Ongoing analysis of LOAD risk genes shows both similar as well as distinct endolysosomal defects underscoring that a possible common endosomal deregulations may originate from different upstream mechanisms.ConclusionTogether, these observations are shedding light on the potential of modulating/restoring endosomal transport regulation as a strategy to alleviate observed early endolysosomal dysfunctions at preclinical stages of AD pathogenesis.

CD2-associated protein (CD2AP) overexpression accelerates amyloid precursor protein (APP) transfer from early endosomes to the lysosomal degradation pathway

A hallmark of Alzheimer's disease (AD) pathology is the appearance of senile plaques, which are composed of β-amyloid (Aβ) peptides. Aβ is produced by sequential cleavages of amyloid precursor protein (APP) by β- and γ-secretases. These cleavages take place in endosomes during intracellular trafficking of APP through the endocytic and recycling pathways. Genome-wide association studies have identified several risk factors for late-onset AD, one of which is CD2-associated protein (CD2AP), an adaptor molecule that regulates membrane trafficking. Although CD2AP's involvement in APP trafficking has recently been reported, how APP trafficking is regulated remains unclear. We sought to address this question by investigating the effect of CD2AP overexpression or knockdown on the intracellular APP distribution and degradation of APP in cultured COS-7 and HEK293 cells. We found that overexpression of CD2AP increases the localization of APP to Rab7-positive late endosomes, and decreases its localization to Rab5-positive early endosomes. CD2AP overexpression accelerated the onset of APP degradation without affecting its degradation rate. Furthermore, nutrient starvation increased the localization of APP to Rab7-positive late endosomes, and CD2AP overexpression stimulated starvation-induced lysosomal APP degradation. Moreover, the effect of CD2AP on the degradation of APP was confirmed by CD2AP overexpression and knockdown in primary cortical neurons from mice. We conclude that CD2AP accelerates the transfer of APP from early to late endosomes. This transfer in localization stimulates APP degradation by reducing the amount of time before degradation initiation. Taken together, these results may explain why impaired CD2AP function is a risk factor for AD.

Astragalus membranaceus-Polysaccharides Ameliorates Obesity, Hepatic Steatosis, Neuroinflammation and Cognition Impairment without Affecting Amyloid Deposition in Metabolically Stressed APPswe/PS1dE9 Mice.

Astragalus membranaceus is commonly used in traditional Chinese medicine for strengthening the host defense system. Astragalus membranaceus-polysaccharides is an effective component with various important bioactivities, such as immunomodulation, antioxidant, anti-diabetes, anti-inflammation and neuroprotection. In the present study, we determine the effects of Astragalus membranaceus-polysaccharides on metabolically stressed transgenic mice in order to develop this macromolecules for treatment of sporadic Alzheimer’s disease, a neurodegenerative disease with metabolic risk factors. Transgenic mice, at 10 weeks old prior to the appearance of senile plaques, were treated in combination of administrating high-fat diet and injecting low-dose streptozotocin to create the metabolically stressed mice model. Astragalus membranaceus-polysaccharides was administrated starting at 14 weeks for 7 weeks. We found that Astragalus membranaceus-polysaccharides reduced metabolic stress-induced increase of body weight, insulin and insulin and leptin level, insulin resistance, and hepatic triglyceride. Astragalus membranaceus-polysaccharides also ameliorated metabolic stress-exacerbated oral glucose intolerance, although the fasting blood glucose was only temporally reduced. In brain, metabolic stress-elicited astrogliosis and microglia activation in the vicinity of plaques was also diminished by Astragalus membranaceus-polysaccharides administration. The plaque deposition, however, was not significantly affected by Astragalus membranaceus-polysaccharides administration. These findings suggest that Astragalus membranaceus-polysaccharides may be used to ameliorate metabolic stress-induced diabesity and the subsequent neuroinflammation, which improved the behavior performance in metabolically stressed transgenic mice.

Xuefu Zhuyu decoction ameliorates obesity, hepatic steatosis, neuroinflammation, amyloid deposition and cognition impairment in metabolically stressed APPswe/PS1dE9 mice

Ethnopharmacological relevanceMetabolic syndrome and vascular dysfunction was suggested to be the risk factors for Alzheimer's disease (AD). Xuefu Zhuyu decoction (XZD) is a traditional Chinese medicine used to treat metabolic syndrome and cardiac-cerebral vascular disease. The effects of XZD on ameliorating metabolic syndrome, amyloid-related pathologies and cognitive impairment in an animal model of AD with metabolic stress was investigated. Materials and methodThe animal model of AD with metabolic stress was created by administrating high-fat diet and a low-dose injection of streptozotocin prior to the appearance of senile plaques in APP/PS1 transgenic mice. The diabesity-associated metabolic changes and AD-related pathological alterations were examined. ResultsWe found that XZD reduced body weight, insulin and leptin level, HOMA-IR, hepatic triglyceride, serum Aβ42 in the metabolic stressed AD animal. XZD also ameliorated oral glucose tolerant, Aβ deposition, astrocyte and microglia activation in the vicinity of plaques, and nesting behavior in the metabolic stressed AD animal. ConclusionThe results of this study suggest that XZD is able to reduce the peripheral metabolic stress-mediated vascular hypoperfusion, neuroinflammation and AD-related pathology in APP/PS1 mice.

Deciphering the Biochemical Pathway and Pharmacokinetic Study of Amyloid βeta-42 with Superparamagnetic Iron Oxide Nanoparticles (SPIONs) Using Systems Biology Approach.

Alzheimer's disease (AD) pathogenesis leads to the appearance of senile plaques due to the production and deposition of the β-amyloid peptide (Aβ). Superparamagnetic iron oxide nanoparticles (SPIONs) have potential role in the detection and imaging of Aβ plaques in AD. SPIONs have shown appropriate potential in the diagnosis and treatment of AD. In the present study, the pharmacokinetics of SPIONs and its effect in the biochemical pathway of AD were analyzed using collected information. During analysis, the interaction of SPIONs with amyloid beta-42 (Aβ42), a biomarker for AD progression, has been shown. Nodes represent the entities and edges represent the relation (interactions) of one node to another node. Aβ42 and their interaction with other entities making up biochemical network are involved in AD mechanism in presence of SPION. The kinetic simulation was done to investigate pharmacokinetics of SPIONs for AD, where concentration was assigned of nanoparticles and other entities were applied as a kinetic irreversible simple Michaelis-Menten or mass action kinetics. Simulation was done in presence and absence of SPIONs to investigate pharmacokinetic effect in AD and explore the mechanism of Aβ42 in presence of SPIONs. This study may lead to better understanding, which is required to target the metabolism of Aß42 peptide, a pivotal player in this pathology.

ApoE4 upregulates the activity of mitochondria-associated ER membranes.

In addition to the appearance of senile plaques and neurofibrillary tangles, Alzheimer's disease (AD) is characterized by aberrant lipid metabolism and early mitochondrial dysfunction. We recently showed that there was increased functionality of mitochondria-associated endoplasmic reticulum (ER) membranes (MAM), a subdomain of the ER involved in lipid and cholesterol homeostasis, in presenilin-deficient cells and in fibroblasts from familial and sporadic AD patients. Individuals carrying the ε4 allele of apolipoprotein E (ApoE4) are at increased risk for developing AD compared to those carrying ApoE3. While the reason for this increased risk is unknown, we hypothesized that it might be associated with elevated MAM function. Using an astrocyte-conditioned media (ACM) model, we now show that ER-mitochondrial communication and MAM function-as measured by the synthesis of phospholipids and of cholesteryl esters, respectively-are increased significantly in cells treated with ApoE4-containing ACM as compared to those treated with ApoE3-containing ACM. Notably, this effect was seen with lipoprotein-enriched preparations, but not with lipid-free ApoE protein. These data are consistent with a role of upregulated MAM function in the pathogenesis of AD and may help explain, in part, the contribution of ApoE4 as a risk factor in the disease.

Molecular Pathogenesis of Sporadic Alzheimer's Disease (AD) and Pharmaceutical Research to Develop a Biomarker for AD Diagnosis

Alzheimer's disease (AD) is the most common senile dementia. One of the pathological characteristics of AD is the appearance of senile plaques composed of amyloid-β (Aβ) depositions. Aβ is generated by consecutive cleavages of Aβ precursor protein (APP) by β- and γ-secretases. The common pathogenesis for familial AD (FAD) is believed to involve misprocessing of APP by γ-secretase, resulting in increased Aβ42 peptide deposition. However, little is known about γ-secretase function in sporadic AD (SAD), which is the major type of AD. This may be because Aβ42 peptide has highly aggregative properties; therefore it is not easy to estimate the quantitative alteration of net Aβ42 in SAD patients. Alcadein is a family of neural type I membrane proteins. Processing of Alcadein by APP α- and γ-secretases results in secretion of non-aggregative peptide, p3-Alc, into CSF and blood. The C-terminuses of Aβ and p3-Alc are altered by FAD-linked genetic mutations in catalytic components of γ-secretase, in association with an increase in minor Aβ and p3-Alc species. Thus p3-Alcs are expected to behave as useful indicators of γ-secretase dysfunction in SAD brain. Quantitative and qualitative analyses of p3-Alcs raise the possibility that γ-secretase dysfunction may exist even in the absence of genetic mutations. p3-Alc peptides may be a novel biomarker for AD and an indicator of γ-secretase dysfunction for drug development.

Impaired cognition and cerebral glucose regulation are associated with astrocyte activation in the parenchyma of metabolically stressed APPswe/PS1dE9 mice

Although metabolic syndrome was suggested to be a risk factor for Alzheimer's disease (AD), the role of metabolic stress in the initiation of AD pathology remains unclear. In this study, metabolic stress was induced by a high-fat diet and low-dose injection of streptozotocin (HFSTZ) before the appearance of senile plaques in APP/PS1 transgenic mice. We found that, HFSTZ treatment exacerbated amyloid beta burden and astrocyte activation in the vicinity of plaques. Moreover, we observed an upregulation of astrocytic S100B expression in the brain parenchyma of HFSTZ-treated APP/PS1 mice concurrent with increased interleukin-6 expression in cerebral microvascular cells. To determine the impact of HFSTZ treatment on brain function, we performed [18F]fludeoxyglucose-positron emission tomography and analyzed nesting behavior. HFSTZ treatment impaired nest construction and cerebral glucose metabolism in several brain regions of APP/PS1 mice during the early stage of AD. These results suggest that HFSTZ-induced peripheral metabolic stress may contribute to vascular inflammation and astrocyte reactivity in the parenchyma and may impair activity of daily living skill and cerebral glucose metabolism in APP/PS1 mice.

Apolipoprotein epsilon 3 alleles are associated with indicators of neuronal resilience

BackgroundEpilepsy is associated with precocious development of Alzheimer-type neuropathological changes, including appearance of senile plaques, neuronal loss and glial activation. As inheritance of APOE ε4 allele(s) is reported to favor this outcome, we sought to investigate neuronal and glial responses that differ according to APOE genotype. With an eye toward defining ways in which APOE ε3 alleles may foster neuronal well-being in epilepsy and/or APOE ε4 alleles exacerbate neuronal decline, neuronal and glial characteristics were studied in temporal lobectomy specimens from epilepsy patients of either APOE ε4,4 or APOE ε3,3 genotype.MethodsTissue and/or cellular expressions of interleukin-1 alpha (IL-1α), apolipoprotein E (ApoE), amyloid β (Aβ) precursor protein (βAPP), synaptophysin, phosphorylated tau, and Aβ were determined in frozen and paraffin-embedded tissues from 52 APOE ε3,3 and 7 APOE ε4,4 (0.25 to 71 years) epilepsy patients, and 5 neurologically normal patients using Western blot, RT-PCR, and fluorescence immunohistochemistry.ResultsTissue levels of IL-1α were elevated in patients of both APOE ε3,3 and APOE ε4,4 genotypes, and this elevation was apparent as an increase in the number of activated microglia per neuron (APOE ε3,3 vs APOE ε4,4 = 3.7 ± 1.2 vs 1.5 ± 0.4; P < 0.05). This, together with increases in βAPP and ApoE, was associated with apparent neuronal sparing in that APOE ε4,4 genotype was associated with smaller neuron size (APOE ε4,4 vs APOE ε3,3 = 173 ± 27 vs 356 ± 45; P ≤ 0.01) and greater DNA damage (APOE ε4,4 vs APOE ε3,3 = 67 ± 10 vs 39 ± 2; P = 0.01). 3) Aβ plaques were noted at early ages in our epilepsy patients, regardless of APOE genotype (APOE ε4,4 age 10; APOE ε3,3 age 17).ConclusionsOur findings of neuronal and glial events, which correlate with lesser neuronal DNA damage and larger, more robust neurons in epilepsy patients of APOE ε3,3 genotype compared to APOE ε4,4 genotype carriers, are consistent with the idea that the APOE ε3,3 genotype better protects neurons subjected to the hyperexcitability of epilepsy and thus confers less risk of AD (Alzheimer's disease).Please see related article: http://www.biomedcentral.com/1741-7015/10/36

An amyloid-β protofibril-selective antibody prevents amyloid formation in a mouse model of Alzheimer's disease

Human genetics link Alzheimer's disease pathogenesis to excessive accumulation of amyloid-β (Aβ) in brain, but the symptoms do not correlate with senile plaque burden. Since soluble Aβ aggregates can cause synaptic dysfunctions and memory deficits, these species could contribute to neuronal dysfunction and dementia. Here we explored selective targeting of large soluble aggregates, Aβ protofibrils, as a new immunotherapeutic strategy. The highly protofibril-selective monoclonal antibody mAb158 inhibited in vitro fibril formation and protected cells from Aβ protofibril-induced toxicity. When the mAb158 antibody was administered for 4 months to plaque-bearing transgenic mice with both the Arctic and Swedish mutations (tg-ArcSwe), Aβ protofibril levels were lowered while measures of insoluble Aβ were unaffected. In contrast, when treatment began before the appearance of senile plaques, amyloid deposition was prevented and Aβ protofibril levels diminished. Therapeutic intervention with mAb158 was however not proven functionally beneficial, since place learning depended neither on treatment nor transgenicity. Our findings suggest that Aβ protofibrils can be selectively cleared with immunotherapy in an animal model that display highly insoluble Aβ deposits, similar to those of Alzheimer's disease brain.

Salvianolic acid B inhibits Aβ fibril formation and disaggregates preformed fibrils and protects against Aβ-induced cytotoxicty

One of the major pathological features of Alzheimer's disease (AD) is the appearance of senile plaques characterized by extracellular aggregation of amyloid β-peptide (Aβ) fibrils. Inhibition of Aβ fibril aggregation is therefore viewed as one possible method to halt the progression of AD. Salvianolic acid B (Sal B) is an active ingredient isolated from Salvia miltiorrhiza, a Chinese herbal medicine commonly used for the treatment of cardiovascular and cerebrovascular disorders. Recent findings show that Sal B prevents Aβ-induced cytotoxicity in a rat neural cell line. To understand the mechanism of Sal B-mediated neuroprotection, its effects on the inhibition of Aβ1–40 fibril formation and destabilization of the preformed Aβ1–40 fibrils were studied. The results were obtained using Thioflavin T fluorescence assay and Aβ aggregating immunoassay. We found that Sal B can inhibit fibril aggregation (IC 50: 1.54–5.37 μM) as well as destabilize preformed Aβ fibril (IC 50: 5.00–5.19 μM) in a dose- and time-dependent manner. Sal B is a better aggregation inhibitor than ferulic acid but less active than curcumin in the inhibition of Aβ1–40 aggregation. In electron microscope study, Sal B-treated Aβ1–40 fibrils are seen in various stages of shortening or wrinkling with numerous deformed aggregates of amorphous structure. Circular dichroism data indicate that Sal B dose dependently prevents the formation of β-structured aggregates of Aβ1–40. Addition of preincubated Sal B with Aβ1–42 significantly reduces its cytotoxic effects on human neuroblastoma SH-SY5Y cells. These results suggest that Sal B has therapeutic potential in the treatment of AD, and warrant its study in animal models.

Evidence against the overexpression of APP in down syndrome

Down syndrome (DS) is the most common genetic disorder with mental retardation and is caused by trisomy 21. By the age of 40 years, virtually all adults with DS have sufficient neuropathology for a diagnosis of Alzheimer's disease (AD), which is characterized by accumulation of amyloid-beta in senile plaques and formation of neurofibrillary tangles. Amyloid-beta derives from a longer precursor protein, APP, whose gene maps to chromosome 21. In DS, the early appearance of senile plaques is commonly associated with the presence of a third copy of the APP gene. Here we show DS brains and trisomic fibroblasts in which APP is not overexpressed, compared to euploid controls, challenging the notion that the widespread amyloid-beta deposits, consistently found in DS individuals, result from an extra copy of APP.

Down-regulation of Endogenous Amyloid Precursor Protein Processing due to Cellular Aging

Processing of amyloid precursor protein (APP) is a well acknowledged central pathogenic mechanism in Alzheimer disease. However, influences of age-associated cellular alterations on the biochemistry of APP processing have not been studied in molecular detail so far. Here, we report that processing of endogenous APP is down-regulated during the aging of normal human fibroblasts (IMR-90). The generation of intracellular APP cleavage products C99, C83, and AICD gradually declines with increasing life span and is accompanied by a reduced secretion of soluble APP (sAPP) and sAPPalpha. Further, the maturation of APP was reduced in senescent cells, which has been shown to be directly mediated by age-associated increased cellular cholesterol levels. Of the APP processing secretases, protein levels of constituents of the gamma-secretase complex, presenilin-1 (PS1) and nicastrin, were progressively reduced during aging, resulting in a progressive decrease in gamma-secretase enzymatic activity. ADAM10 (a disintegrin and metalloprotease 10) and BACE (beta-site APP-cleaving enzyme) protein levels exhibited no age-associated regulation, but interestingly, BACE enzymatic activity was increased in aged cells. PS1 and BACE are located in detergent-resistant membranes (DRMs), well structured membrane microdomains exhibiting high levels of cholesterol, and caveolin-1. Although total levels of both structural components of DRMs were up-regulated in aged cells, their particular DRM association was decreased. This age-dependent membrane modification was associated with an altered distribution of PS1 and BACE between DRM and non-DRM fractions, very likely affecting their APP processing potential. In conclusion, we have found a significant modulation of endogenous APP processing and maturation in human fibroblasts caused by age-associated alterations in cellular biochemistry.

Conditions of Alzheimer‐type dementia in the old‐old and oldest‐old patients with special reference to extreme conditions of brain aging

A neuropathological study on 1540 consecutive autopsy brains ranging from 60 to 107 years of age revealed the following points. (1) Of the of the demented cases of the plaque‐predominant type, 93% were complicated with multiple tiny cortical infarcts. They showed a tendency for dementia to develop before or after the appearance or worsening of a systemic disorder such as cardiovascular disease, respiratory infection and cancer. However, there was no case showing Alzheimer‐type dementia (ATD). (2) The plaque‐predominant type might be an extreme condition of brain aging in terms of senile plaques (SP). It is likely that although the pathological appearance of SP alone is not responsible for dementia, its coexistence with multiple cortical infarcts could be the cause of dementia. Therefore, this type should be distinguished from ATD. (3) Primary hippocampal degeneration could also be an extreme condition of brain aging in terms of neurofibrillary tangles. This condition was different pathologically from the hippocampal lesion in ATD. (4) Several characteristics of old‐old and oldest‐old patients were clarified.

Immune mechanism in senile plaque formation

Alzheimer disease (AD) is characterized by the appearance of two very different lesions, senile plaques and neurofibrillary tangles (NFTs). The pathological process which causes the disease must be responsible for both, but how they are linked is still a mystery. Neurofibrillary tangles develop intracellularly and involve the appearance of abnormally phosphorylated forms of tau. Senile plaques develop extracellularly with the deposition of beta-amyloid protein (BAP), a component of the larger amyloid precursor protein (APP). Neurofibrillary tangles are not unique to AD. They appear in a number of degenerative neurological diseases in which senile plaques are absent. This is an argument against NFTs causing the appearance of senile plaques. Conversely, extracellular deposits of BAP occur in areas where NFTs do not develop, indicating that BAP deposits, by themselves, do not cause NFTs. However, when senile plaques “mature”, dystrophic neuntes which contain abnormally phosphorylated tau are always present. Thus, it is possible that NFTs evolve from developing senile plaques.

Alterations in Alzheimer's Disease—Associated Protein in Alzheimer's Disease Frontal and Temporal Cortex

Alzheimer's disease (AD)-associated protein is present in brain and cerebrospinal fluid of patients with AD but not in adult, nondemented, normal controls. This protein may represent an abnormal epitope of the "tau" microtubule-associated protein and has been detected before the appearance of senile plaques and neurofibrillary tangles. The amount of AD-associated protein in the frontal and temporal cortices in 93 cases of neuropathologically confirmed AD was compared with the amount that was present in 20 cases without AD. The amount of AD-associated protein was significantly increased in the cases of AD for both brain regions compared with that in the cases without AD. The presence of high levels of this protein is a useful adjunct, postmortem marker of the presence of AD and may eventually lead to tests that allow early detection of individuals at risk for this disease.