Effects of an Intravenously Administered Soluble Amyloid Precursor Protein-Alpha Gene Therapy on Neuropathology in the 5xFAD Mouse Model of Alzheimer's Disease

Alzheimer’s Disease (AD) is characterised by progressive cognitive decline associated with amyloid-β (Aβ) deposition, tau pathology, synaptic dysfunction and neuroinflammation. While most therapeutic strategies target Aβ clearance, another area of focus is enhancing neuroprotective pathways. Soluble amyloid precursor protein-alpha (sAPPα), generated via α-secretase cleavage of APP, exhibits many neuroprotective properties and has emerged as a potential disease-modifying candidate for AD treatment. The present study evaluated whether systemic intravenous delivery of an AAV.CAP-B10 vector encoding human sAPPα could modify neuropathological features in the 5xFAD mouse model of familial AD. Widespread GFP expression was observed providing evidence of successful central nervous system transduction. Consistent with the established phenotype of 5xFAD mice, immunofluorescence analysis showed robust genotype effects across amyloid and glial markers (6E10, Iba1, CD68, GFAP, C3), but no modulation of microglial or astrocytic activation was found. No effect of sAPPα treatment on amyloid plaque burden soluble Aβ_1-40 or Aβ_1-42 concentrations, or insoluble Aβ_1-42 concentration were found, however a reduction in insoluble Aβ_1-40 was found in treated 5xFAD mice. The selective reduction of insoluble Aβ_1-40 suggests partial engagement of sAPPα with amyloid dynamics despite there being no plaque reduction. These findings support the interpretation that sAPPα may function primarily as a modulator of cognitive resilience and that its therapeutic impact may be constrained in models of AD characterised by rapid supraphysiological Aβ overproduction. These findings highlight the importance of aligning therapeutic mechanisms with disease model severity in preclinical gene therapy research.