STTT：AAV基因治疗阿尔茨海默病

Core Viewpoint - Alzheimer's disease (AD) is a destructive neurodegenerative disorder characterized by gradual cognitive decline, necessitating therapies that can slow or halt its progression [2][6]. Group 1: Current Treatments and Limitations - Currently, only a few FDA-approved monoclonal antibodies targeting amyloid-beta (Aβ) are available for early-stage Alzheimer's treatment, such as Lecanemab and Donanemab, which show efficacy in reducing amyloid burden but have limited impact on disease progression [2]. - The focus on Aβ alone is insufficient to address the progressive nature of Alzheimer's disease [2]. Group 2: Gene Therapy as a Promising Strategy - Gene therapy that enhances intrinsic neuroprotective pathways presents a promising new strategy to slow neurodegenerative changes and prevent further cognitive decline [3][6]. - Caveolin-1 (Cav-1), a membrane scaffolding protein, regulates various growth-promoting and survival signaling pathways, indicating its potential in Alzheimer's treatment [6]. Group 3: Research Findings - A recent study from the University of California, San Diego, demonstrated that delivering Cav-1 via AAV9 to symptomatic Alzheimer's mouse models can mitigate cognitive loss and pathological transcriptome changes [4][5]. - The study involved administering SynCav1 to symptomatic Alzheimer's mouse models (PSAPP and APPKI) and showed that it maintained hippocampal-dependent memory abilities [7][8]. - Transcriptomic analysis indicated that the profiles of PSAPP-SynCav1 mice were similar to those of age-matched wild-type mice, with downregulation of neurodegenerative pathways and upregulation of synaptic and cognitive-related pathways [8][10]. Group 4: Mechanisms of Action - The delivery of SynCav1 to the hippocampus during the symptomatic stage protected learning and memory abilities, with increased expression levels of p-CaMKII and p-CREB in primary cortical neurons, suggesting enhanced neuronal and synaptic activity [10]. - Activity-dependent neuroprotective protein (ADNP) was identified as a potential mediator of SynCav1's neuroprotective effects, retaining PAC1R, a known regulator of ADNP expression [11][12].