Hippocampal delivery of neurotrophic factor-α1/carboxypeptidase E gene prevents neurodegeneration, amyloidosis, memory loss in Alzheimer's Disease male mice.
Lan XiaoXuyu YangVinay Kumar SharmaDaniel AbebeY Peng LohPublished in: Molecular psychiatry (2023)
Alzheimer's Disease (AD) is a prevalent neurodegenerative disease characterized by tau hyperphosphorylation, Aβ1-42 aggregation and cognitive dysfunction. Therapeutic agents directed at mitigating tau aggregation and clearing Aβ1-42, and delivery of growth factor genes (BDNF, FGF2), have ameliorated cognitive deficits, but these approaches did not prevent or stop AD progression. Here we report that viral-(AAV) delivery of Neurotrophic Factor-α1/Carboxypeptidase E (NF-α1/CPE) gene in hippocampus at an early age prevented later development of cognitive deficits as assessed by Morris water maze and novel object recognition assays, neurodegeneration, and tau hyperphosphorylation in male 3xTg-AD mice. Additionally, amyloid precursor protein (APP) expression was reduced to near non-AD levels, and insoluble Aβ1-42 was reduced significantly. Pro-survival proteins: mitochondrial Bcl2 and Serpina3g were increased; and mitophagy inhibitor Plin4 and pro-inflammatory protein Card14 were decreased in AAV-NF-α1/CPE treated versus untreated AD mice. Thus NF-α1/CPE gene therapy targets many regulatory components to prevent cognitive deficits in 3xTg-AD mice and has implications as a new therapy to prevent AD progression by promoting cell survival, inhibiting APP overexpression and tau hyperphosphorylation.
Keyphrases
- gene therapy
- signaling pathway
- growth factor
- oxidative stress
- cerebrospinal fluid
- genome wide
- lps induced
- high fat diet induced
- pi k akt
- cognitive decline
- transcription factor
- working memory
- poor prognosis
- binding protein
- copy number
- type diabetes
- nuclear factor
- metabolic syndrome
- cerebral ischemia
- high throughput
- stem cells
- dna methylation
- protein protein
- mesenchymal stem cells
- genome wide analysis
- blood brain barrier