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 sAPP␣. 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 ␥-secretase complex, presenilin-1 (PS1) and nicastrin, were progressively reduced during aging, resulting in a progressive decrease in ␥-secretase enzymatic activity. ADAM10 (a disintegrin and metalloprotease 10) and BACE (-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 detergentresistant 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.Aging is the most prevailing risk factor of Alzheimer disease, even though the biochemical basis of this association is unknown. A significant pathological feature of Alzheimer disease is the appearance of senile plaques that are composed primarily of amyloid  (A), 2 a 38 -42-amino-acid peptide derived from proteolytic processing of the ubiquitously expressed amyloid precursor protein (APP) (1). At least three APP processing secretases are identified. ADAM10 (␣-secretase) is involved in non-amyloidogenic processing and cleaves APP within the A domain, whereby release of A is prevented and soluble sAPP␣ is secreted (2). Amyloidogenic processing is driven by BACE (-secretase), which cleaves APP at the N-terminal site of the A domain (3). Subsequently, a complex of presenilin, nicastrin, anterior pharynx defective-1 and presenilin enhancer-2 (␥-secretase complex) cleaves the generated C-terminal fragments (CTFs) C83 or C99 at the C-terminal site of the A domain (4 -6). This results in the generation of the APP intracellular domain (AICD), and in the amyloidogenic pathway, A is released (7,8).BACE and the ␥-secretase complex have been well described to be associated to deterge...
The description of the data set shown in the printed issue as Fig. 1 actually corresponds to the legend labeled as Fig. 2, and the description of the data set shown in the printed issue as Fig. 2 actually corresponds to the legend labeled as Fig. 1.
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