Neuronal aging potentiates beta-amyloid generation via amyloid precursor protein endocytosis

Aging increases the risk of Alzheimers disease (AD). During normal aging synapses decline and {beta}-Amyloid (A{beta}) accumulates. An A{beta} defective clearance with aging is postulated as responsible for A{beta} accumulation, although a role for increased A{beta} production with aging can also lead to A{beta} accumulation. To test this hypothesis, we established a long-term culture of primary mouse neurons that mimics neuronal aging (lysosomal lipofuscin accumulation and synapse decline). Intracellular endogenous A{beta}42 accumulated in aged neurites due to increased amyloid-precursor protein (APP) processing. We show that APP processing is up-regulated by a specific age-dependent increase in APP endocytosis. Endocytosed APP accumulated in early endosomes that, in turn were found augmented in aged neurites. APP processing and early endosomes up-regulation was recapitulated in vivo. Finally, we found that inhibition of A{beta} production reduced the decline in synapses in aged neurons. We propose that potentiation of APP endocytosis by neuronal aging increases A{beta} production, which contributes to aging-dependent decline in synapses.\n\nSummaryHow aging increases the risk of Alzheimers disease is not clear. We show that normal neuronal aging increases the intracellular production of {beta}-amyloid, due to an upregulation of the amyloid precursor protein endocytosis. Importantly, increased A{beta} production contributes to the aging-dependent synapse loss.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=76 SRC=\"FIGDIR/small/616540v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (16K):\norg.highwire.dtl.DTLVardef@1f124e1org.highwire.dtl.DTLVardef@ac34e0org.highwire.dtl.DTLVardef@1c37a2aorg.highwire.dtl.DTLVardef@898e91_HPS_FORMAT_FIGEXP M_FIG C_FIG