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

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.