Reversible CRISPRa/i Therapy for Alzheimer's Disease: Gene Regulation for Neuroregeneration and Endocannabinoid Modulation

Alzheimer’s disease is a progressive neurodegenerative condition characterized by
the accumulation of amyloid-beta plaques, tau tangles, and chronic neuroinflammation, leading to cognitive decline and neuronal loss. Current treatments provide only symptomatic relief, without addressing the underlying causes. In this article, we propose a novel gene therapy strategy using reversible CRISPR activation and interference
(CRISPRa/i) to modulate key pathways in neurodegeneration, neuroregeneration, and the endogenous cannabinoid system. The approach involves silencing genes such as APP, PSEN1/2, and APOE4, activating neuroregenerative factors including BDNF, NGF, and Klotho, and inducing the endogenous production of neuroprotective cannabinoids by upregulating biosynthetic genes such as FAAH, DAGLA, and NAPEPLD. The proposed therapy aims not only to halt disease progression but also to restore synaptic function and cognitive performance, offering a promising path toward personalized and
regenerative treatment of Alzheimer’s.