Autophagy in Alzheimer's Disease Pathogenesis
R.A. Nixon
NYU School of Medicine/Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA
Cellular protein turnover is mediated largely by the proteasome and
lysosomal system. While proteasome activity declines during aging and
Alzheimers disease (AD), the lysosomal system is mobilized in
vulnerable neurons early in the disease. Macroautophagy, a major
pathway to lysosomes for the turnover of organelles and long-lived
proteins, involves the sequestration and degradation of these
cytoplasmic constituents within a series of vesicular compartments
(autophagic vacuoles or AVs). Macroautophagy is induced early in AD
and starting before beta-amyloid deposition in the PS1-APP mouse model
of AD, which may initially support regeneration/repair and protect
neurons from accumulating cytotoxic factors. We find, however, that
neuronal autophagy may ultimately fail in AD. Early AVs
(autophagosomes) and late AVs progressively accumulate in high numbers
in dendrites of affected neurons and become the principal organelles
within dystrophic neurites, suggesting that AV transport and the
maturation of AVs to lysosomes are impeded. The lysosomal pathology in
AD and beta-amyloid mouse models is potentiated by presenilin-1
mutations (PS1) that cause more severe early-onset forms of AD.
Fibroblasts from patients with PS1-FAD also accumulate AVs abnormally
when macroautophagy is induced. Surprisingly, however, the turnover of
proteins by macroautophagy, as measured by metabolic labeling, is
markedly reduced in PS-FAD fibroblast lines and nearly completely
blocked in blastocysts from PS1/2 gene deleted mice, indicating that PS
may play a role in macroautophagy and that FAD-causing mutations of PS
confer a loss of macroautophagic function. Slowing
autophagic/lysosomal protein degradation in the brains of PS/APP mice
by inhibiting cathepsins in vivo accelerates neurodegeneration,
possibly by impeding turnover of abnormal and potentially toxic
proteins and releasing cathepsins. Finally, purified AVs are highly
enriched in presenilin 1, nicastrin, and presenilin dependent
gamma-ecretase activity and contain the other components needed for
A-beta generation. Inducing or inhibiting macroautophagy in intact
cells by modulating mTOR kinase induces parallel changes in the extent
of macroautophagy induction, AV proliferation, and A-beta production.
Our results, therefore, link amyloidogenic and cell survival pathways
through macroautophagy, which is activated and possibly dysfunctional
in AD. Supported by the NIA and Alzheimers Association.
Key words:
lysosomes, proteasome, cathepsins, Alzheimer's disease, amyloid
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