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Age-dependent autophagy impairment risks Alzheimer’s disease due to ULK1 reduction

ABSTRACT: Why age is the primary driver of the most common dementia-Alzheimer’s disease (AD)? Autophagy plays fundamental roles in cellular homeostasis, metabolic energetics, and in maintaining cellular resilience such as via eliminating damaged mitochondria. It is proposed that impaired autophagy leads to compromised catabolic degradation of amyloid beta (Aβ) and Tau pathologies, the disease-defining pathologies of AD; however, molecular mechanisms on whether and if yes, why reduced autophagy during ageing and its contribution to AD, especially in human samples, are largely elusive. By using serum and CSF samples from a healthy ageing cohort (n = 22 with 4-year follow up samples) and an AD cohort (n = 391), we show that the abundance of ULK1 protein in serum and CSF decreases with increasing age and is extremely lower in AD patients than in age-matched controls. In a large number of postmortem human brain samples (n = 72), expression of ULK1 in entorhinal cortical and hippocampal neurons in AD patients is significantly lower than in neurons from cognitive normal controls. To investigate whether ULK1 reduction is a bystander or cause/risk of AD, we generated a ubiquitously ULK1-ov mouse model and an AAV-based CA1 neuronal ULK1-ov mouse model in Aβ-bearing background; ULK1 overexpression stimulates autophagic and phagocytic degradation of Aβ, improves mitochondrial quality, thereby delaying progressive cognitive loss. Similarly, in hTau.P301S mice, overexpression of ULK1 inhibits Tau pathology and inhibits memory loss; mechanistically, ULK1 upregulation increases autophagy which increases cellular NAD+, leading to the inhibition of acetylated Tau174 (a cause of Tau pathology) through the NAD+/SIRT1 axis. ULK1 is likely a druggable target for AD as small molecule activators of ULK1 antagonize AD progression which is dependent on PINK1- and FUNDC1-related mitophagy. We propose age-dependent autophagy impairment risks AD due to ULK1 reduction, opening a new window for anti-AD therapeutics.

ORGANISM(S): Mus musculus

PROVIDER: GSE263411 | GEO | 2026/03/04

REPOSITORIES: GEO

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Project description:Alzheimer’s Disease (AD) is the most common cause of age-related dementia and the sixth leading cause of death in the United States. AD neuropathology is primarily characterized by the accumulation of extracellular beta-amyloid (Aβ) plaques and intraneuronal neurofibrillary tau tangles. In addition to these hallmark AD pathologies, many other important pathological changes occur in the brains of AD patients, including synaptic and neuronal loss and neuroinflammation. Most recently, genome-wide association studies (GWAS) have provided substantial new evidence that immune dysfunction may contribute to the development and progression of AD. To date over 60 GWAS loci have been identified and almost two thirds of these genes are highly expressed in microglia, the resident innate immune cell of the brain. These genetic discoveries have in turn inspired many new studies of microglial biology and the role of these cells in AD. In contrast, the role of the adaptive immunity in AD remains understudied, despite evidence that many of AD risk genes are also highly expressed in T and B cells. To investigate the role of T cell infiltration in AD, we examined T cells from immune-deficient AD mice via bone marrow transplantation studies using flow cytometry and immunohistochemistry; and from immune-intact transgenic AD model mice using flow cytometry, immunohistochemistry, and single-cell RNA sequencing. Our experiments demonstrate that multiple T cell subtypes infiltrate the AD brain, and that effector memory CD8 T cells are specifically enriched in response to Aβ pathology or a combination of Aβ and tau pathologies. Single-cell sequencing analysis revealed high expression of over 40 AD risk genes between several T cell sub-populations, implying a need for more research of these T cell phenotypes in AD development. Additionally, T-cell receptor (TCR) sequencing revealed increased clonal expansion of T cells from mice that developed Aβ pathology or Aβ and tau pathology, suggesting amyloid-driven recruitment and clonal expansion of T cells in these mice. Ultimately, this study demonstrates the crucial importance of investigating the role of T cells in AD and provides a guide for future experiments to continue to enhance our understanding of AD immunology.

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Age-dependent autophagy impairment risks Alzheimer’s disease due to ULK1 reduction

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