We have characterized amyloid beta peptide (Abeta) concentration, Abeta deposition, paired helical filament formation, cerebrovascular amyloid angiopathy, apolipoprotein E (ApoE) allotype, and synaptophysin concentration in entorhinal cortex and superior frontal gyrus of normal elderly control (ND) patients, Alzheimer's disease (AD) patients, and high pathology control (HPC) patients who meet pathological criteria for AD but show no synapse loss or overt antemortem symptoms of dementia. The measures of Abeta deposition, Abeta-immunoreactive plaques with and without cores, thioflavin histofluorescent plaques, and concentrations of insoluble Abeta, failed to distinguish HPC from AD patients and were poor correlates of synaptic change. By contrast, concentrations of soluble Abeta clearly distinguished HPC from AD patients and were a strong inverse correlate of synapse loss. Further investigation revealed that Abeta40, whether in soluble or insoluble form, was a particularly useful measure for classifying ND, HPC, and AD patients compared with Abeta42. Abeta40 is known to be elevated in cerebrovascular amyloid deposits, and Abeta40 (but not Abeta42) levels, cerebrovascular amyloid angiopathy, and ApoE4 allele frequency were all highly correlated with each other. Although paired helical filaments in the form of neurofibrillary tangles or a penumbra of neurites surrounding amyloid cores also distinguished HPC from AD patients, they were less robust predictors of synapse change compared with soluble Abeta, particularly soluble Abeta40. Previous experiments attempting to relate Abeta deposition to the neurodegeneration that underlies AD dementia may have failed because they assayed the classical, visible forms of the molecule, insoluble neuropil plaques, rather than the soluble, unseen forms of the molecule.

Summary Neurodegenerative tauopathies characterized by hyperphosphorylated tau include frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and Alzheimer's disease (AD). Reducing tau levels improves cognitive function in mouse models of AD and FTDP-17, but the mechanisms regulating the turnover of pathogenic tau are unknown. We found that tau is acetylated and that tau acetylation prevents degradation of phosphorylated tau (p-tau). Using two antibodies specific for acetylated tau, we showed that tau acetylation is elevated in patients at early and moderate Braak stages of tauopathy. Histone acetyltransferase p300 was involved in tau acetylation and the class III protein deacetylase SIRT1 in deacetylation. Deleting SIRT1 enhanced levels of acetylated-tau and pathogenic forms of p-tau in vivo, likely by blocking proteasome-mediated degradation. Inhibiting p300 with a small molecule promoted tau deacetylation and eliminated p-tau associated with tauopathy. Modulating tau acetylation could be a new therapeutic strategy to reduce tau-mediated neurodegeneration.

No abstract

Whether elevated ␤-secretase (BACE) activity is related to plaque formation or amyloid ␤ peptide (A␤) production in Alzheimer's disease (AD) brains remains inconclusive. Here, we report that we used sandwich enzyme-linked immunoabsorbent assay to quantitate various A␤ species in the frontal cortex of AD brains homogenized in 70% formic acid. We found that most of the A␤ species detected in rapidly autopsied brains (<3 h) with sporadic AD were A␤ 1-x and A␤ 1-42, as well as A␤x-42. To establish a linkage between A␤ levels and BACE, we examined BACE protein, mRNA expression and enzymatic activity in the same brain region of AD brains. We found that both BACE mRNA and protein expression is elevated in vivo in the frontal cortex. The elevation of BACE enzymatic activity in AD is correlated with brain A␤ 1-x and A␤1-42 production. To examine whether BACE elevation was due to mutations in the BACE-coding region, we sequenced the entire ORF region of the BACE gene in these same AD and nondemented patients and performed allelic association analysis. We found no mutations in the ORF of the BACE gene. Moreover, we found few changes of BACE protein and mRNA levels in Swedish mutated amyloid precursor protein-transfected cells. These findings demonstrate correlation between A␤ loads and BACE elevation and also suggest that as a consequence, BACE elevation may lead to increased A␤ production and enhanced deposition of amyloid plaques in sporadic AD patients. A lzheimer's disease (AD) is the most common cause of dementia in the population Ͼ60 years of age. Senile plaques and paired helical filaments are the two hallmarks of the brain pathology of AD (1-3). Amyloid ␤ peptide (A␤), a major protein component (4 kDa) of the senile plaque (4), is generated from amyloid precursor protein (APP) by enzymatic digestion involving ␤-secretase (BACE) and ␥-secretase activities.The mechanisms of A␤ accumulation in the majority of AD patients (sporadic AD) remain unclear although a minority of AD patients carry mutations in the APP and presenilin (PS) genes, which lead to an increase in A␤ production (5). A␤ is the cleavage product from APP by two enzymes: BACE and ␥-secretase. BACE is a transmembrane aspartyl protease and has recently been cloned and characterized (6-10). Overexpression of BACE in transfected cells increases the amount of C99 and C89, which are both BACE-cleavage products. More BACE-cleaved APP products were found in the Swedish mutation (APPsw) as compared with that in wild-type substrate (APPwt) (6). The BACE cleavage occurs at the known ␤-cleavage sites of APP, Asp 1, and Glu 11 (6-10). The role of BACE played in A␤ production in vitro might explain the higher production of A␤ peptide in AD brains and the early onset of Swedish familial AD. Recently, we and other investigators demonstrated higher BACE expression levels found in sporadic AD brains compared with healthy age-matched controls (11-13). A␤ accumulation in the AD brain is a chronic process and a small elevation of BACE might lead to a significant increase in ...

Estrogens are the primary female sex hormones and play important roles in both reproductive and non-reproductive systems. Estrogens can be synthesized in non-reproductive tissue as liver, heart, muscle, bone and brain. The tissue-specific estrogen synthesis is consistent with a diversity of estrogen actions. Here, we will focus on tissue and cell-specific estrogen synthesis and estrogen receptor signaling. This review will include three parts: (I) tissue and cell-specific estrogen synthesis and metabolism, (II) tissue and cell-specific distribution of estrogen receptors and signaling and (III) tissue-specific estrogen function and related disorders, including cardiovascular diseases, osteoporosis, Alzheimer's disease and Parkinson disease. This comprehensive review provides new insights into estrogens by giving a better understanding of the tissue-specific estrogen effects and their roles in various diseases.

Beta-site APP-cleaving enzyme (BACE) is required for production of the Alzheimer's disease (AD)-associated Abeta protein. BACE levels are elevated in AD brain, and increasing evidence reveals BACE as a stress-related protease that is upregulated following cerebral ischemia. However, the molecular mechanism responsible is unknown. We show that increases in BACE and beta-secretase activity are due to posttranslational stabilization following caspase activation. We also found that during cerebral ischemia, levels of GGA3, an adaptor protein involved in BACE trafficking, are reduced, while BACE levels are increased. RNAi silencing of GGA3 also elevated levels of BACE and Abeta. Finally, in AD brain samples, GGA3 protein levels were significantly decreased and inversely correlated with increased levels of BACE. In summary, we have elucidated a GGA3-dependent mechanism regulating BACE levels and beta-secretase activity. This mechanism may explain increased cerebral levels of BACE and Abeta following cerebral ischemia and existing in AD.

Much evidence indicates that women have a higher risk of developing Alzheimer's disease (AD) than do men. The reason for this gender difference is unclear. We hypothesize that estrogen deficiency in the brains of women with AD may be a key risk factor. In rapidly acquired postmortem brains from women with AD, we found greatly reduced estrogen levels compared with those from age-and gender-matched normal control subjects; AD and control subjects had comparably low levels of serum estrogen. We examined the onset and severity of AD pathology associated with estrogen depletion by using a gene-based approach, by crossing the estrogen-synthesizing enzyme aromatase gene knockout mice with APP23 transgenic mice, a mouse model of AD, to produce estrogen-deficient APP23 mice. Compared with APP23 transgenic control mice, estrogen-deficient APP23 mice exhibited greatly reduced brain estrogen and early-onset and increased ␤ amyloid peptide (A␤) deposition. These mice also exhibited increased A␤ production, and microglia cultures prepared from the brains of these mice were impaired in A␤ clearance͞degradation. In contrast, ovariectomized APP23 mice exhibited plaque pathology similar to that observed in the APP23 transgenic control mice. Our results indicate that estrogen depletion in the brain may be a significant risk factor for developing AD neuropathology.amyloid deposition ͉ aromatase ͉ transgenic animal N europathological hallmarks of Alzheimer's disease (AD) include significant deposition of extracellular ␤ amyloid peptide (A␤) and presence of neurofibrillary tangles in the brain (1). A␤ is derived from the two-step enzymatic processing of amyloid precursor protein (APP) in which ␤-secretase (BACE) cleaves the ␤-site of APP to release the N terminus of A␤, and the ␥-secretase protein complex cleaves the ␥-site of APP to release the C terminus of A␤ (2, 3). Overproduction and progressive deposition of A␤ are known to underlie, in part, A␤ plaque formation, a key pathologic feature of AD. The initial cleavage of APP by BACE is critical for A␤ associated with AD neuropathology (4). Recent studies have shown that BACE activity increases with age and is elevated in AD brains (5, 6).Impaired A␤ clearance and͞or degradation may also contribute to A␤ plaque formation. Our previous findings support this hypothesis: Microglia isolated from AD brains have impaired phagocytic activity, leading to reduced A␤ clearance (7). Other groups have found that cytoplasmic A␤ granules in the plaque-associated glia and microglia participate in the clearance of A␤ in A␤-immunized AD patients and APP transgenic mice (8, 9).Two enzymes are involved in A␤ degradation and clearance: insulin-degrading enzyme (IDE) and neprilysin (NEP). IDE is expressed in high concentrations in the brain. Besides degrading insulin and several regulatory peptides, IDE also degrades the intracellular domain of APP and is responsible for degrading and clearing A␤ from the brain (10, 11). Indeed, genetic linkage studies have shown that late-onset AD loci on chromosome 1...

The tumor necrosis factor type 1 death receptor (TNFR1) contributes to apoptosis. TNFR1, a subgroup of the TNFR superfamily, contains a cytoplasmic death domain. We recently demonstrated that the TNFR1 cascade is required for amyloid β protein (Aβ)–induced neuronal death. However, the function of TNFR1 in Aβ plaque pathology and amyloid precursor protein (APP) processing in Alzheimer's disease (AD) remains unclear. We report that the deletion of the TNFR1 gene in APP23 transgenic mice (APP23/TNFR1−/−) inhibits Aβ generation and diminishes Aβ plaque formation in the brain. Genetic deletion of TNFR1 leads to reduced β-secretase 1 (BACE1) levels and activity. TNFR1 regulates BACE1 promoter activity via the nuclear factor-κB pathway, and the deletion of TNFR1 in APP23 transgenic mice prevents learning and memory deficits. These findings suggest that TNFR1 not only contributes to neurodegeneration but also that it is involved in APP processing and Aβ plaque formation. Thus, TNFR1 is a novel therapeutic target for AD.