A novel mechanism of autophagy-lysosome pathway impairment in Alzheimer disease-associated neuropathogenesis: Role of AKAP11-mediated autophagy and PKA signaling

Alzheimer's disease (AD) is the most prevalent and deleterious neurological disorder characterized by the accumulation of amyloid β (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated Tau (p-Tau) in the brain. Accumulating evidence indicates that impairment of autophagy-lysosome pathway may significantly contribute to AD pathogenesis, yet the exact mechanisms remain unclear. Cyclic AMP-dependent protein kinase A (PKA) is crucial for memory formation but it is downregulated in the brains of AD patients. Our recent studies identified AKAP11, a protein that anchors PKA, as a novel autophagy receptor that regulates PKA activity through the selective degradation of its inhibitory subunit, PKA-RI. Notably, we previously reported that AKAP11 and other autophagy-related genes are significantly downregulated in the BA36-parahippocampal gyrus of AD patients. These results suggest a potential
involvement of AKAP11-mediated autophagy and PKA signaling in AD pathogenesis.
To explore the role of AKAP11 in AD, we knocked down Akap11 in the hippocampus of mouse. We found that, compared to controls, mice with Akap11 deficiency in the hippocampus (hereafter referred to as Akap11KD-hippo mice) exhibit AD-associated pathologies, including cognitive impairment, synaptic dysfunction, and tauopathy, correlated with increased PKA-RI and decreased TFEB-mediated autophagy in the hippocampus. Activation of TFEB has shown neuroprotective roles in AD mouse models by enhancing autophagy. Our preliminary results indicate that, compared to vehicle treatment, TFEB activator significantly improves cognitive function and restores autophagy in Akap11KD-hippo mice. Additionally, in Tau P301S mice, we observed a significant reduction in AKAP11, along with increased PKA-RI and decreased autophagy, suggesting disruption of AKAP11-mediated autophagy and PKA signaling in tauopathy mice. Based on these results, we hypothesize that AKAP11 regulates AD-associated pathogenesis potentially by controlling PKA activity and TFEB-mediated
autophagy in mice.
This proposal will further fulfill three objectives to test this hypothesis.
(1) To investigate whether activation of AKAP11-mediated autophagy and PKA signaling can ameliorate AD-associated pathology in Akap11KD-hippo mice;
(2) To determine the role of AKAP11-mediated autophagy and PKA signaling in Tau P301S mice;
(3) To dissect the mechanism by which AKAP11 regulates TFEB-mediated autophagy.
The successful accomplishment of this proposal will uncover a novel role for AKAP11- mediated autophagy in regulating AD-associated pathology in mice; elucidate the molecular mechanisms by which AKAP11 influences these processes; and advance our understanding of how autophagy impairment contributes to AD pathogenesis by disrupting the PKA signaling pathway. In long term, the discoveries from this project will provide a potential therapeutic target for AD treatment.