Neuron‐Targeted Caveolin‐1 gene therapy preserves hippocampal neuroplasticity and memory in Alzheimer’s Disease mice

Alzheimer’s disease (AD) is a neurodegenerative condition with severe cognitive deficits which is closely correlated with loss of synapses and neurons, thus, targeting neuroprotective mechanisms specifically to neuronal cells that changes the synaptic strength and resistance to toxic Ab and the following inflammation response may restore functional neuronal and synaptic plasticity independent of removing toxic amyloid species. One potential molecular target is caveolin‐1 (Cav‐1), a membrane/lipid raft (MLR) scaffolding protein that organizes synaptic proteins and associated synaptic signaling components (e.g., neurotrophin and neurotransmitter receptors). Recent pre‐clinical and clinical evidence showed that Cav‐1 and Cav‐1 associated signaling complexes (TrkA, TrkB, GluN2B, dopaminergic, cholinergic receptors, and adenylyl cyclase) were decreased in degenerating neurons from a variety of neurodegenerative conditions which included AD, CTE, and ALS. Here we show that Cav‐1 expression decreases in the hippocampus occurs at early stages of cognitive loss (6 months (m)) and correlates to the progression of pathological of AD. Furthermore, one‐time hippocampal administration of adeno‐associated virus that encodes neuron‐targeted Cav‐1 using a synapsin promoter (AAV‐SynCav1) at 3 months (m) preserves learning and memory in 9 and 11 m old amyloid‐positive APPSwePS1d9 mice (i.e., AD). At 9 month, immunoblot and proteomic analysis of hippocampus MLR confirmed decreased Cav‐1 in AD‐SynRFP and preserved Cav‐1 in AD‐SynCav1. Bioinformatics analysis identified 80 up‐regulated proteins in AD‐SynCav1 MLR and gene ontology analysis found several proteins are related to synaptic function (Shisa9, an AMPAR regulatory protein critical for memory; Piccolo, scaffolding protein in synaptic active zones) and cholesterol homeostasis (Kiaa1468, Ap2a2). At 11 m, Golgi‐Cox histology demonstrated that SynCav1 preserved CA1 dendritic arbor in AD mice compared to AD‐SynRFP mice. Electron microscopy (EM) of CA1 apical dendrites revealed preserved ultrastructural indicators of synaptic plasticity (e.g., total type I excitatory synapses, presynaptic vesicles per axonal bouton, normal dendritic spine morphology), preserved mossy fiber area, and preserved myelinated CA3 Schaffer collaterals in 11 m AD‐SynCav1 mice. These findings offer important proof‐of‐concept evidence for the use of neuron‐targeted Cav‐1 (i.e., SynCav1) gene therapy to future AAV‐9‐based clinical trials in AD as well as other neurodegenerative diseases. Support or Funding Information Veterans Affairs Merit Award from the Department of Veterans Affairs BX003671 (B. P. Head); National Institutes of Health, Bethesda, MD, U.S.A., NS073653 (B. P. Head); and GM085179 (P. M. Patel).SynCav1 gene delivery preserves fear learning and contextual memory recall in 9 month and 11 month‐old APPSwePS1d9 mice, respectively.SynCav1 gene delivery preserved hippocampal Cav‐1 expression and MLR‐localized synaptic proteins in 9 month‐old APPSwePS1d9 mice.