AAV-Based Intracerebral Administration of BDNF Promotes Myelin Repair and Cognitive Improvement After Cuprizone-Induced Demyelination

Abstract

Multiple sclerosis (MS) is a chronic neurological disorder involving immune-mediated demyelination and neurodegeneration in the central nervous system (CNS). Current therapies primarily target inflammation, with limited strategies to promote remyelination or neural repair. This study explores the therapeutic potential of Brain-Derived Neurotrophic Factor (BDNF) delivered via an adeno-associated virus (AAV) vector to enhance remyelination and improve cognitive function in a subchronic cuprizone (CPZ)-induced demyelination mouse model. Sixty female C57BL/6 mice were used, with half receiving a 7-week CPZ diet to induce oligodendrocyte loss. After demyelination, mice were treated with AAV-BDNF, AAV-eGFP, or saline injections into the corpus callosum (CC), followed by a 5-week recovery phase. Behavioral assessments revealed improved cognitive performance with BDNF treatment, demonstrated by increased latency in passive avoidance tests. Immunofluorescence analysis showed increased proliferation and maturation of oligodendrocyte progenitor cells, with higher PDGFRα and CC1 markers, alongside elevated MBP. Transmission electron microscopy (TEM) indicated thicker myelin sheaths and a higher percentage of myelinated axons in AAV-BDNF-treated mice. Mitochondrial analyses revealed that BDNF treatment preserved mitochondrial integrity, with reduced swelling and improved structural regularity. Inflammatory markers showed no differences in Iba1 but indicated a trend of reduced astrocytic activation with BDNF. These results demonstrate that AAV-BDNF therapy enhances remyelination, myelin integrity, mitochondrial structure, and cognitive function in a CPZ model, underscoring its potential for treating MS. BDNF-based strategies may offer innovative avenues to improve neurological recovery and address unmet needs in MS management.