Autophagy Induction and Autophagosome Clearance in Neurons: Relationship to Autophagic Pathology in Alzheimer's Disease
Open accessAbstract
Macroautophagy, a major pathway for organelle and protein turnover, has been implicated in the neurodegeneration of Alzheimer's disease (AD). The basis for the profuse accumulation of autophagic vacuoles (AVs) in affected neurons of the AD brain, however, is unknown. In this study, we show that constitutive macroautophagy in primary cortical neurons is highly efficient, because newly formed autophagosomes are rapidly cleared by fusion with lysosomes, accounting for their scarcity in the healthy brain. Even after macroautophagy is strongly induced by suppressing mTOR (mammalian target of rapamycin) kinase activity with rapamycin or nutrient deprivation, active cathepsin-positive autolysosomes rather than LC3-II-positive autophagosomes predominate, implying efficient autophagosome clearance in healthy neurons. In contrast, selectively impeding late steps in macroautophagy by inhibiting cathepsin-mediated proteolysis within autolysosomes with cysteine- and aspartyl-protease inhibitors caused a marked accumulation of electron-dense double-membrane-limited AVs, containing cathepsin D and incompletely degraded LC3-II in perikarya and neurites. Similar structures accumulated in large numbers when fusion of autophagosomes with lysosomes was slowed by disrupting their transport on microtubules with vinblastine. Finally, we find that the autophagic vacuoles accumulating after protease inhibition or prolonged vinblastine treatment strongly resembled AVs that collect in dystrophic neurites in the AD brain and in an AD mouse model. We conclude that macroautophagy is constitutively active and highly efficient in healthy neurons and that the autophagic pathology observed in AD most likely arises from impaired clearance of AVs rather than strong autophagy induction alone. Therapeutic modulation of autophagy in AD may, therefore, require targeting late steps in the autophagic pathway.
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Baseline autophagy in neurons constitutively operates at a highly processive level, such that maturing autophagosomes are rapidly incorporated into autolysosomes, which represent the majority of the autophagic vesicle population after autophagy induction or flux inhibition.
“Baseline autophagy in neurons constitutively operates at a highly processive level, such that maturing autophagosomes are rapidly incorporated into autolysosomes, which represent the majority of the autophagic vesicle population after autophagy induction or flux inhibition [379].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [379]
Aβ is targeted for autophagy-dependent degradation within the lysosome, explaining why activation of autophagy reduces the burden of Aβ plaques in rodents.
“Aβ is targeted for autophagy‐dependent degradation within the lysosome, explaining why activation of autophagy reduces the burden of Aβ plaques in rodents (Boland et al, 2008; Menzies et al, 2017; Meng et al, 2019).”
From Autophagy in major human diseases (2021) · cites this paper as Boland et al, 2008
Disruption of autophagic flux and failure of autophagosomes to fuse with lysosomes leads to a build-up of vesicles seen in dystrophic neurites and cell bodies in AD, CBD and PSP, as well as in tauopathy models.
“Disruption of autophagic flux and a failure of autophagosomes to fuse with lysosomes leads to a build-up of vesicles, which can be seen in dystrophic neurites and cell bodies in AD, CBD and PSP, as well as in tauopathy models73–76.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [73]
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- Authors
- Boland, B., Kumar, A., Lee, S., Platt, F. M., Wegiel, J., Yu, W. H., & Nixon, R. A.
- Affiliations
- Nathan Kline Institute for Psychiatric Research (US)
- University of Oxford (GB)
- Columbia University (US)
- Corresponding author
- Boland, B.
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-07-02
- Volume
- 28
- Issue
- 27
- Pages
- 6926-6937
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2676733
- OpenAlex
- W2128101513
- Cited by
- 1,119
- References
- 56
- Citations by year
- 2026: 36 · 2025: 43 · 2024: 47 · 2023: 38 · 2022: 62 · 2021: 82 · 2020: 80 · 2019: 92 · 2018: 70 · 2017: 75 · 2016: 77 · 2015: 70 · 2014: 61 · 2013: 59 · 2012: 77
- FWCI
- 36.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Funders
- Alzheimer's Association
- Wellcome Trust
- National Institute on Aging (AG017617, P01AG017617)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- macroautophagy, autophagosome clearance, autophagosomes, Alzheimer's disease, cortical neurons, cathepsin D, autolysosomes, mTOR inhibition, rapamycin, nutrient deprivation, cysteine protease inhibitors, aspartyl protease inhibitors, LC3-II, autophagosome-lysosome fusion, microtubule transport, dystrophic neurites, neurodegeneration
- MeSH terms
- Alzheimer Disease, Animals, Animals, Newborn, Autophagy, Brain, Cathepsins, Cells, Cultured, Lysosomes, Microtubule-Associated Proteins, Neurons, Peptide Hydrolases, Phagosomes, Protein Kinases, Vinblastine, Neurites, Rats, Sprague-Dawley, Tubulin Modulators, Rats, TOR Serine-Threonine Kinases
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