Abstract
The greatest risk factor for Alzheimer's disease (AD) is advanced age, but the reason for this association remains unclear. Amyloid-β (Aβ) is produced from amyloid precursor protein (APP) primarily after APP is internalized by clathrin-mediated or clathrin-independent endocytosis. Changes in endocytosis in AD have been identified. We hypothesized that endocytic protein expression is altered during ageing, thus influencing the likelihood of developing AD by increasing Aβ production. We explored how levels of endocytic proteins, APP, its metabolites, secretase enzymes, and tau varied with age in cortical brain samples from men of three age ranges (young [20-30], middle aged [45-55], and old [70-90]) with no symptoms of dementia. Aβ40 and Aβ42 were significantly increased in old brains, while APP and secretase expression was unaffected by age. Phosphorylated GSK3β increased significantly with age, a possible precursor for neurofibrillary tangle production, although phosphorylated tau was undetectable. Significant increases in clathrin, dynamin-1, AP180, Rab-5, caveolin-2, and flotillin-2 were seen in old brains. Rab-5 also increased in middle-aged brains prior to changes in Aβ levels. This age-related increase in endocytic protein expression, not described previously, suggests an age-related upregulation of endocytosis which could predispose older individuals to develop AD by increasing APP internalization and Aβ generation.
Highlights
Alzheimer's disease (AD) is the most common form of dementia accounting for an estimated 60-80% of all cases [1]
We have shown that the levels of several clathrin-mediated endocytosis (CME) proteins including clathrin, dynamin-2 and PICALM were significantly higher in aged 22-month transgenic Tg2576 mice expressing the Swedish mutation of human amyloid precursor protein (APP) compared to age-matched wild-type mice [23]
We hypothesised that the expression of endocytic proteins is altered during ageing predisposing older individuals to develop AD. We have investigated this hypothesis using brain samples from young, middle-aged and old men with no known history of dementia to examine the expression of a range of endocytic proteins involved in CME and clathrinindependent endocytosis (CIE), APP metabolites and tau
Summary
Alzheimer's disease (AD) is the most common form of dementia accounting for an estimated 60-80% of all cases [1]. The brain pathology of AD is characterised by two hallmarks; extracellular senile plaques made of amyloid-beta (Aβ) and intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated tau [2]. Aβ is produced in the amyloidogenic pathway where amyloid precursor protein (APP) is cleaved by β-secretase APP-cleaving enzyme (BACE1) to liberate soluble APPβ (sAPPβ) and the intracellular β-carboxy-terminal fragment (βCTF) [2]. Γ-Secretase cleaves βCTF to produce Aβ and a C-terminal fragment [2,3], primarily after APP has undergone endocytosis [4]. In the non-amyloidogenic pathway α-secretase cleaves APP within Aβ to release soluble APP (sAPPα) precluding the production of Aβ (5 ). A microtubuleassociated protein essential for protein transport, becomes hyper-phosphorylated in AD due to the activity of a number of kinases including glycogen synthase kinase3β (GSK3β) [7]
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