Proteins Involved in Endocytosis Are Upregulated by Ageing in the Normal Human Brain: Implications for the Development of Alzheimer's Disease

The greatest risk factor for Alzheimer's disease (AD) is advanced age, but the reason for this association remains unclear. Amyloid-beta (A beta) 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 A beta 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. A beta 40 and A beta 42 were significantly increased in old brains, while APP and secretase expression was unaffected by age. Phosphorylated GSK3 beta 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 A beta 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 A beta generation.