Evaluation of hippocampal DLGAP2 overexpression on cognition, synaptic function, and dendritic spine structure in a translationally relevant AD mouse model

INTRODUCTION Developing effective therapeutics for Alzheimer's disease (AD) requires a better understanding of the molecular drivers of the disease. Our previous work nominated DLGAP2 as a modifier of age‐related cognitive decline and risk for AD. We tested the hypothesis that overexpression of DLGAP2 in the hippocampus would protect against cognitive and synaptic deficits in a susceptible F1 5XFAD model. METHODS DLGAP2 was overexpressed in the hippocampus of F1 hybrid 5XFAD and non‐transgenic littermates using a viral approach. Cognitive function, electrophysiological properties, and dendritic spine morphology were assessed at 6 and 14 months of age. RESULTS DLGAP2 overexpression impaired synaptic plasticity and exacerbated AD‐related memory deficits but had minimal effect on spine structure or intrinsic neuronal properties. DISCUSSION We highlight the complex role of DLGAP2 in AD pathology. Targeted interventions involving postsynaptic proteins must consider potential adverse effects on synaptic integrity and cognitive performance, particularly in the context of AD. Highlights DLGAP2 overexpression accelerates AD‐related impairment of contextual fear acquisition and memory. DLGAP2 overexpression impairs synaptic plasticity prior to AD‐related memory impairment, but not intrinsic excitability. Effect of DLGAP2 overexpression on thin spine density was blunted in AD mice from in vivo dendritic spine results that were replicated in cultured rodent neurons.