Synapsin-caveolin-1 gene therapy preserves neuronal and synaptic morphology and prevents neurodegeneration in a mouse model of AD

Shanshan Wang; Joseph S Leem; Sonia Podvin; Vivian Hook; Natalia Kleschevnikov; Paul Savchenko; Mehul Dhanani; Kimberly Zhou; Isabella C Kelly; Tong Zhang; Atsushi Miyanohara; Phuong Nguyen; Alexander Kleschevnikov; Steve L Wagner; John Q Trojanowski; David M Roth; Hemal H Patel; Piyush M Patel; Brian P Head

doi:10.1016/j.omtm.2021.03.021

Synapsin-caveolin-1 gene therapy preserves neuronal and synaptic morphology and prevents neurodegeneration in a mouse model of AD

Mol Ther Methods Clin Dev. 2021 Mar 29:21:434-450. doi: 10.1016/j.omtm.2021.03.021. eCollection 2021 Jun 11.

Authors

Shanshan Wang^{1

2}, Joseph S Leem^{1

2}, Sonia Podvin³, Vivian Hook³, Natalia Kleschevnikov^{1

2}, Paul Savchenko², Mehul Dhanani^{1

2}, Kimberly Zhou^{1

2}, Isabella C Kelly², Tong Zhang⁴, Atsushi Miyanohara^{1

2}, Phuong Nguyen⁵, Alexander Kleschevnikov⁵, Steve L Wagner^{1

5}, John Q Trojanowski⁶, David M Roth^{1

2}, Hemal H Patel^{1

2}, Piyush M Patel^{1

2}, Brian P Head^{1

2}

Affiliations

¹ Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
² Department of Anesthesiology, University of California San Diego, San Diego, CA 92161, USA.
³ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.
⁴ Campus Microscopy & Imaging Facility (CMIF)/Microscopy Shared Resource (MSR), The Ohio State University, OH, USA.
⁵ Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
⁶ Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104-4283, USA.

Abstract

Alzheimer's disease (AD) is the most common form of neurodegeneration and cognitive dysfunction in the elderly. Identifying molecular signals that mitigate and reverse neurodegeneration in AD may be exploited therapeutically. Transgenic AD mice (PSAPP) exhibit learning and memory deficits at 9 and 11 months, respectively, with associated decreased expression of caveolin-1 (Cav-1), a membrane/lipid raft (MLR) scaffolding protein necessary for synaptic and neuroplasticity. Neuronal-targeted gene therapy using synapsin-Cav-1 cDNA (SynCav1) was delivered to the hippocampus of PSAPP mice at 3 months using adeno-associated virus serotype 9 (AAV9). Bilateral SynCav1 gene therapy was able to preserve MLRs profile, learning and memory, hippocampal dendritic arbor, synaptic ultrastructure, and axonal myelin content in 9- and 11-month PSAPP mice, independent of reducing toxic amyloid deposits and astrogliosis. Our data indicate that SynCav1 gene therapy may be an option for AD and potentially in other forms of neurodegeneration of unknown etiology.

Keywords: Alzheimer’s disease; MLRs; PSAPP; caveolin-1; gene therapy; membrane lipid raft; synaptic ultrastructure.

Abstract

Grants and funding