Researchers here assess a compensatory approach to the neurodegeneration of Alzheimer's disease, meaning an enhancement of the ability of cells to operate in the face of damage rather than addressing the damage itself. This can inevitably only slow progression of the condition, and is not a path to a curative therapy. Nonetheless, tinkering with cell metabolism in order to slow disease progression is arguably the dominant approach to the development of new therapies. The research community needs to do better than this if we're to see major advances in the treatment of aging and age-related conditions.
Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by progressive synaptic loss and cognitive decline. Gene therapy that augments intrinsic neuroprotective pathways offers a promising strategy to mitigate neurodegeneration and prevent further cognitive loss. Caveolin-1 (Cav-1), a membrane lipid raft (MLR) scaffolding protein, regulates multiple pro-growth and pro-survival signaling pathways within plasmalemmal microdomains. Previously, we showed that AAV9-Synapsin-promoted Cav-1 (SynCav1) delivered to presymptomatic AD mice preserved cognitive functions and MLR-associated neurotrophic signaling. However, the therapeutic potential of SynCav1 delivered at the symptomatic stage of AD had not been tested. Therefore, the current study investigated the effect of hippocampal SynCav1 delivery at symptomatic age in two distinct preclinical AD models of amyloid pathology: PSAPP and APPKI mice.
Our results demonstrated that SynCav1 delivery to PSAPP and APPKI mice at symptomatic age consistently preserved hippocampal-dependent memory. Transcriptome profiling revealed that PSAPP-SynCav1 mice exhibited a similar transcript profile to age-matched wild-type mice. Gene Ontology enrichment analysis indicated downregulation of neurodegeneration-specific pathways and upregulation of synaptic and cognitive-related pathways in PSAPP-SynCav1 mice. In vitro, SynCav1-transfected mouse primary cortical neurons exhibited increased p-CaMKII and p-CREB expression, suggesting that SynCav1 may protect the central nervous system by enhancing neuronal and synaptic activity. Furthermore, activity-dependent neuroprotective protein (ADNP) was identified as a potential candidate mediating SynCav1's neuroprotective effects on cognition. Subcellular membrane fractionation revealed that SynCav1 preserved MLR-localized pituitary adenylate cyclase-activating polypeptide type I receptor (PAC1R), a well-known regulator of ADNP expression. Together, these findings highlight SynCav1 as a unique and promising gene therapy candidate in the treatment of AD.
Link: https://doi.org/10.1038/s41392-025-02258-z
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