Opstogenetic stimulation of dorsolateral striatum to improve spatial memory deficit in AD mice

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. Early damages are observed in hippocampal regions, which are key areas for declarative memory formation. Further on, they also spread to neocortical regions. Hallmark features of AD include abnormal accumulation of amyloid-beta (Aβ) plaques, hyperphosphorylated Tau (p-Tau), neuroinflammation, and disrupted neurotransmission. Despite these changes, in some AD patient cognitive function is delayed or reduced. This phenomenon is often linked to neural compensation, whereby unaffected brain regions become hyperactive to support cognitive function. Recent studies suggest that the dorsolateral striatum (DLS), a region not canonically involved in memory processes, may contribute to long-term spatial memory encoding. In this study, we used the APP23 transgenic mouse model of AD to explore the therapeutic potential of activating non-affected brain regions, as DLS, on spatial memory performance. First, we performed molecular characterization of APP23 at 6 months of age, confirming AD-like pathology via increased levels of Aβ, phosphorylated Tau (p-Tau), and GFAP expression, indicating astrocytic reactivity. We then expressed a stabilized step-function opsin (SSFO) in the DLS to enable prolonged neuronal activation during saptial memory acquisition/cosolidation phases. Behavioral performance was assessed in Object Displacement and Morris Water Maze (MWM) tests. Compared to control mice, stimulated AD mice showed improved memory performance in the recall (probe) phase in MWM but not in Object Displacement. These findings suggest that enhancing activity in preserved regions like the DLS may reduce cognitive deficits in AD mice.