The role of autophagy in Aβ and tau metabolism in Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by amyloid plaques composed of amyloid beta (Aβ) peptides, and neurofibrillary tangles (NFTs) containing hyperphosphorylated and misfolded tau proteins. Aβ is generated intracellularly by proteolytic processing of amyloid precursor protein (APP). Furthermore, the cell’s major waste management system, autophagy, has been shown to be impaired in AD. This has been observed by an accumulation of double membranous autophagic vacuoles (AVs) in AD postmortem brains. The impaired function of the autophagic system in AD might be detrimental because autophagy helps to eliminate the disease-causing Aβ and tau species. Consequently, autophagy has been suggested as a potential therapeutic target for AD. Understanding the autophagy-mediated disease mechanisms is crucial to establish autophagy-related therapies. This thesis investigated the bidirectional interplay between autophagy and AD pathologies.

Paper I evaluated the autophagic impairment in AppNL-F and AppNL-G-F knock-in AD mouse models exhibiting several key AD pathologies including Aβ amyloidosis, neuroinflammation, synaptic alteration, and memory impairment. AppNL-G-F mice displayed autophagic alterations resembling those of the human AD brain. AppNL-F mice show slower Ab pathology development than AppNL-G-F mice and the alteration in the autophagic system was limited to an accumulation of AVs around amyloid plaques at the late stage of pathology. Finally, this study established the App knock-in mouse models as tools to examine the contribution of Aβ pathology to autophagy impairment in AD.

Paper II aimed to shed light on the involvement of autophagy in APP transport and processing. By establishing the retention using selective hooks (RUSH) system for fluorescently labeled mCherry-APP-EGFP, this study provides a tool to trace APP trafficking from the ER in a systematic way. Autophagy inhibition, either through knockout (KO) of autophagy-related gene 9 (ATG9) or treatment with an Unc-51- like kinase inhibitor, enhanced the localization of mCherry-APP-EGFP at the plasma membrane and resulted in increased processing of mCherry-APP-EGFP. Those findings contribute to the understanding that functional autophagy is crucial for homeostatic APP turnover and orchestrates APP’s intracellular transport.

Paper III elucidated the in vivo role of autophagy and tau pathology, specifically in excitatory neurons of a novel Atg7 cKO tauopathy P301L mouse model. The deletion of autophagy by Atg7 cKO exacerbated tau pathology, as evidenced by an increased number of NFT-like structures and a higher amount of insoluble tau aggregates. This was further accompanied by elevated tau seeding capacity isolated from autophagy-deficient brain homogenates. Finally, the increased tau pathology in autophagy-deficient tauopathy mice worsened spatial memory assessed by modified Y maze. This study provides a novel mouse model to illuminate the role of autophagy in tau metabolism and highlights the importance of functional autophagy in preventing tau aggregation and spreading.

List of scientific papers

I. Richeng Jiang, Makoto Shimozawa, Johanna Mayer, Simone Tambaro, Rakesh Kumar, Axel Abelein, Bengt Winblad, Nenad Bogdanovic, Per Nilsson. Autophagy Impairment in App Knock-in Alzheimer’s Model Mice. Frontiers in Aging Neuroscience. (2022) 14.
https://doi.org/10.3389/fnagi.2022.878303

II. Johanna Mayer, Dominik Boeck, Michelle Werner, Daniela Frankenhauser, Stephan Geley, Hesso Farhan, Makoto Shimozawa, Per Nilsson. Inhibition of autophagy alters intracellular transport of APP resulting in increased APP processing. Traffic. (2024) 25: e12934.
https://doi.org/10.1111/tra.12934

III. Makoto Shimozawa, Johanna Mayer, Delia-Denisa Dunca, Federico Picciau, Alexander Sandberg, Erik Berger, Sofia Miranda Fernandes, Marina Chikaraishi, Luca Sartori, Martin Hallbeck, Per Nilsson. Autophagy deficiency increases seeding propensity of tau and aggravates tau pathology and memory impairment in a tauopathy mouse model. [Manuscript]