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Loss of ATG7 in microglia impairs UPR, triggers ferroptosis, and weakens amyloid pathology control
Zhangying Cai1, Shoutang Wang1,2, Siyan Cao1
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
Abstract:
Microglia impact brain development, homeostasis, and pathology. One important microglial function in Alzheimer's disease (AD) is to contain proteotoxic amyloid-β (Aβ) plaques. Recent studies reported the involvement of autophagy-related (ATG) proteins in this process. Here, we found that microglia-specific deletion of Atg7 in an AD mouse model impaired microglia coverage of Aβ plaques, increasing plaque diffusion and neurotoxicity. Single-cell RNA sequencing, biochemical, and immunofluorescence analyses revealed that Atg7 deficiency reduces unfolded protein response (UPR) while increasing oxidative stress. Cellular assays demonstrated that these changes lead to lipoperoxidation and ferroptosis of microglia. In aged mice without Aβ buildup, UPR reduction and increased oxidative damage induced by Atg7 deletion did not impact microglia numbers. We conclude that reduced UPR and increased oxidative stress in Atg7-deficient microglia lead to ferroptosis when exposed to proteotoxic stress from Aβ plaques. However, these microglia can still manage misfolded protein accumulation and oxidative stress as they age.
Insights
Deleting autophagy gene Atg7 in microglia worsened Alzheimer's disease (AD) pathology by causing microglial ferroptosis. This highlights Atg7's role in protecting microglia from amyloid-beta plaque toxicity.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Microglia are crucial for brain health and disease, playing a role in containing amyloid-beta (Aβ) plaques in Alzheimer's disease (AD).
- Autophagy-related (ATG) proteins are implicated in microglial functions related to protein homeostasis.
Purpose of the Study:
- To investigate the role of the autophagy gene Atg7 in microglia during Alzheimer's disease progression.
- To determine the impact of Atg7 deficiency on microglial response to amyloid-beta plaques and its contribution to neurotoxicity.
Main Methods:
- Generated a mouse model with microglia-specific Atg7 deletion in an AD context.
- Utilized single-cell RNA sequencing, biochemical assays, and immunofluorescence.
- Performed cellular assays to assess microglial responses.
Main Results:
- Microglia-specific Atg7 deletion impaired Aβ plaque coverage, increasing plaque diffusion and neurotoxicity.
- Atg7 deficiency reduced the unfolded protein response (UPR) and increased oxidative stress in microglia.
- These cellular changes led to lipoperoxidation and ferroptosis (a form of programmed cell death) in microglia exposed to Aβ plaques.
Conclusions:
- Reduced UPR and increased oxidative stress in Atg7-deficient microglia trigger ferroptosis when encountering Aβ plaque proteotoxic stress.
- Despite ferroptosis under AD conditions, Atg7-deficient microglia retain some capacity to manage aging-related protein misfolding and oxidative stress.
