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First published online November 21, 2007
doi: 10.1242/10.1242/jcs.019265

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Autophagy, amyloidogenesis and Alzheimer disease

Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, Departments of Psychiatry and Cell Biology, NYU School of Medicine, New York, NY 10016, USA

View larger version (94K): [in this window] [in a new window]   Fig. 1. Pathology of Alzheimer disease. (A) The two hallmark features of Alzheimer disease, -amyloid plaques (arrowheads) and neurofibrillary tangles (arrows) in AD brain are revealed by the Bielschowsky silver stain. (B) Antibodies against paired-helical-filament (PHF) tau (arrows) and -amyloid (arrowheads) label PHF-containing neurites associated with amyloid deposits. (C,D) Cathepsin D antibodies decorate lysosomes in cell bodies of (C, arrow) pyramidal neurons and in dystrophic neurites associated with plaques (C, arrowheads; and D). (E) Dystrophic neurites (arrows) are grossly enlarged compared with neurites in normal brain (inset) by electron microscopy. Abnormal swollen neurites contain predominantly AVs of varying morphologies. By contrast, AVs are rare in normal brain (inset). Bar, 500 nm. Panel E reprinted by permission (Nixon et al., 2005).

View larger version (116K): [in this window] [in a new window]   Fig. 2. Ultrastructure of AVs in AD brain. (A-C) Dystrophic neurites are filled predominantly with (A) AVs, including large double-membrane limited immature AVs, such as autophagosomes containing multiple smaller compartments (B) or multilamellar structures (C, arrowhead), and single-membrane vesicles containing electron-dense intraluminal materical, which correspond to late AVs (autophagolysosomes, amphisomes) or lysosomes (C, arrow). The latter structures are immunogold labeled by antibodies to cathepsin D, which identifies them as autophagolysosomes. AVs in AD brain are similar to AVs isolated from livers of mice treated with vinblastine to slow autophagosome-lysosome fusion (panels D,E). Bars, 500 nm. Reprinted with permission (Nixon et al., 2005).

View larger version (23K): [in this window] [in a new window]   Fig. 3. Functional domains of APP and major sites of proteolytic cleavage (, , ) by APP secretases. sAPP, soluble APP fragment; AICD, APP intracellular domain.

View larger version (62K): [in this window] [in a new window]   Fig. 4. (A) Schematic of the lysosomal system illustrating the endocytic and autophagic pathways to the (A) lysosome and the ultrastructure of (B-E) specific compartments. The major organelles of the autophagic pathway are a pre-autophagic structure (PAS), which sequesters large areas of cytoplasm within a double membrane-limited autophagosome (AP). This organelle receives hydrolases by fusing with either a lysosome to form an autophagolysosome (AL) or with a late endosome/multivesicular body (LE/MVB) to form an amphisome (Gordon and Seglen, 1998; Liou et al., 1997). Efficient digestion of substrates within these compartments in both cases yields a lysosome containing mainly acid hydrolases. (B) Internalized materials entering the endocytic pathway are directed to early (sorting) endosomes (EE), which mature to LE/MVB. (C) An autophagosome, which is hydrolase-negative, contains recognizable but partially digested organelle compartments. (D) Another type of immature AV is double-membrane limited and contains heterogeneous intraluminal materials, including other organelles. (E) Following further substrate digestion, the content of an autolysosomes is amorphous and less dense. Complete digestion of substrates within autolysosomes ultimately yields lysosomes, which are smaller, less dense vesicles containing mainly lysosomal hydrolases (E). Bar, 500 nm.

View larger version (78K): [in this window] [in a new window]   Fig. 5. Macroautophagy is impaired in the PS1-APP mouse model of AD. (A, arrows) Immature AVs accumulate during the early evolution of pathology in a dendrite. (B) Punctate structures exhibiting strong LC3 immunofluorescence can be seen in neurites of PS1-APP mice (arrows) and especially in the swollen dystrophic dendrites of cortical pyramidal neurons. (C) Development of neuritic dystrophy in AD brain. Endocytic trafficking and autophagy are both normally active in neuronal processes. Nascent AVs mature to autophagolysosomes during their retrograde transport, fusing with anterogradely transported lysosomes. Pathological AV accumulation is associated with inhibited retrograde AV transport and impaired autophagosome-lysosome fusion. Fusion of some accumulated AV compartments with the plasma membrane may contribute to local membrane expansion. Bars, 500 nm (A); 10 µm (B). Panels A and B reprinted with permission (Yu et al., 2006).

View larger version (130K): [in this window] [in a new window]   Fig. 6. Presenilin and A peptide selectively immunolocalize to AVs within dystrophic neurites of PS1/APP mice. (A) Antibodies to PS1 strongly decorate neuritic plaques. (B) Immunogold-EM reveals that PS1 localizes principally to the limiting membranes of the AV, while mitochondria (Mito) or plasma membrane (PM) are unlabeled. (C) A42 immunoreactivity is detected within AVs of dystrophic neurites by silver-enhanced immunogold labeling. Reprinted with permission (Yu et al., 2005).

View larger version (21K): [in this window] [in a new window]   Fig. 7. (A-E) Proposed models of AV accumulation leading to elevated A levels. (A) Usual progression from autophagosomes (AP) to autophagolysosomes (APL) to lysosomes (L). Conditions that result in AV build up are expected to promote A generation and accumulation. (B,C) These conditions include impaired and delayed maturation of autophagosomes to (B) lysosomes or (C) acute induction of autophagy. (D,E) Within neurons, AVs normally mature to lysosomes efficiently as they reach the perikaryon and are usually rare (D). In AD, however, AVs in neurites fail to mature completely to lysosomes either as a cause or consequence of disrupted proteolytic clearance and/or retrograde transport of AVs, thereby promoting the accumulation of AVs capable of generating A and the delayed degradation of A by lysosomes (E). The continued capacity of immature AVs to fuse with other membranous structures, including possibly the plasma membrane, is a possible basis for slow exocytic release of AV contents, including A, from the dystrophic neurite.