Macroautophagy deficiency mediates age-dependent neurodegeneration through a phospho-tau pathway
Open accessAbstract
Background: Macroautophagy is an evolutionarily conserved mechanism for bulk intracellular degradation of proteins and organelles. Pathological studies have implicated macroautophagy defects in human neurodegenerative disorders of aging including Alzheimer’s disease and tauopathies. Neuronal deficiency of macroautophagy throughout mouse embryonic development results in neurodevelopmental defects and early postnatal mortality. However, the role of macroautophagy in mature CNS neurons, and the relationship with human disease neuropathology, remains unclear. Here we describe mice deficient in an essential macroautophagy component, Atg7, specifically within postnatal CNS neurons. Results: Postnatal forebrain-specific Atg7 conditional knockout (cKO) mice displayed age-dependent neurodegeneration and ubiquitin- and p62-positive inclusions. Phosphorylated tau was significantly accumulated in Atg7 cKO brains, but neurofibrillary tangles that typify end-stage human tauopathy were not apparent. A major tau kinase, glycogen synthase kinase 3β (GSK3β), was also accumulated in Atg7 cKO brains. Chronic pharmacological inhibition of tau phosphorylation, or genetic deletion of tau, significantly rescued Atg7-deficiency-mediated neurodegeneration, but did not suppress inclusion formation. Conclusions: These data elucidate a role for macroautophagy in the long-term survival and physiological function of adult CNS neurons. Neurodegeneration in the context of macroautophagy deficiency is mediated through a phospho-tau pathway.
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The autophagic system and endosome/lysosome pathways are compromised in AD brains.
“Consistent with this, the autophagic system and endosome/lysosome pathways are compromised in AD brains, and chronic disturbance of this system is thought to contribute to protein accumulation and neurodegeneration [85–87].”
From Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity (2016) · cites this paper as [86]
The Background reports macroautophagy defects in brain sections from patients with AD and discusses disruption of the macroautophagy–lysosomal pathway. It also presents defective protein degradation as a possible contributor to pathological inclusions. The cited passages do not establish that the endosomal pathway is compromised in AD brains. (LLM, conf=0.84)
Experimental — accuracy not yet measuredChronic disturbance of the autophagic/endosome-lysosome system is thought to contribute to protein accumulation and neurodegeneration.
“Consistent with this, the autophagic system and endosome/lysosome pathways are compromised in AD brains, and chronic disturbance of this system is thought to contribute to protein accumulation and neurodegeneration [85–87].”
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- Authors
- Inoue, K., Rispoli, J., Kaphzan, H., Klann, E., Chen, E. I., Kim, J., Komatsu, M., & Abeliovich, A.
- Affiliations
- Columbia University Irving Medical Center (US)
- New York University (US)
- Stony Brook University (US)
- Tokyo Metropolitan Institute of Medical Science (JP)
- Corresponding author
- Abeliovich, Asa
- Venue
- Molecular Neurodegeneration
- Published
- 2012-09-21
- Volume
- 7
- Issue
- 1
- Pages
- 48-48
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC3544596
- OpenAlex
- W2103004596
- Cited by
- 168
- References
- 8
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 8 · 2023: 11 · 2022: 30 · 2021: 16 · 2020: 12 · 2019: 14 · 2018: 10 · 2017: 6 · 2016: 14 · 2015: 9 · 2014: 9 · 2013: 11 · 2012: 1
- FWCI
- 6.44
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Michael J. Fox Foundation for Parkinson's Research
- Kanae Foundation for the Promotion of Medical Science
- National Institute on Aging
- National Institute of Neurological Disorders and Stroke (R01NS060876, R01NS064433)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- macroautophagy, ATG7, age-related neurodegeneration, tau phosphorylation, glycogen synthase kinase-3β, tauopathy, ubiquitin-positive inclusions, p62, Alzheimer's disease, neurodevelopmental defects, conditional knockout mice
- MeSH terms
- Autophagy-Related Protein 7, Aging, Animals, Autophagy, Immunohistochemistry, Microtubule-Associated Proteins, Nerve Degeneration, Neurons, Phosphorylation, Signal Transduction, Prosencephalon, tau Proteins, Mice, Knockout, Microscopy, Electron, Transmission, Mice
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