Noncanonical function of an autophagy protein prevents spontaneous Alzheimer's disease.
Bradlee L HeckmannBrett J W TeubnerEmilio Boada RomeroBart TummersClifford S GuyPatrick FitzgeraldUlrike MayerSimon CardingStanislav S ZakharenkoThomas WilemanDouglas R GreenPublished in: Science advances (2020)
Noncanonical functions of autophagy proteins have been implicated in neurodegenerative conditions, including Alzheimer's disease (AD). The WD domain of the autophagy protein Atg16L is dispensable for canonical autophagy but required for its noncanonical functions. Two-year-old mice lacking this domain presented with robust β-amyloid (Aβ) pathology, tau hyperphosphorylation, reactive microgliosis, pervasive neurodegeneration, and severe behavioral and memory deficiencies, consistent with human disease. Mechanistically, we found this WD domain was required for the recycling of Aβ receptors in primary microglia. Pharmacologic suppression of neuroinflammation reversed established memory impairment and markers of disease pathology in this novel AD model. Therefore, loss of the Atg16L WD domain drives spontaneous AD in mice, and inhibition of neuroinflammation is a potential therapeutic approach for treating neurodegeneration and memory loss. A decline in expression of ATG16L in the brains of human patients with AD suggests the possibility that a similar mechanism may contribute in human disease.
Keyphrases
- endothelial cells
- cell death
- signaling pathway
- oxidative stress
- endoplasmic reticulum stress
- traumatic brain injury
- working memory
- induced pluripotent stem cells
- cognitive decline
- inflammatory response
- adipose tissue
- spinal cord injury
- lipopolysaccharide induced
- pluripotent stem cells
- lps induced
- spinal cord
- amino acid
- mild cognitive impairment