Dysplasia of cortical capillaries as the origin of Alzheimer’s disease: experimental evidence from APP/PS1

To investigate the time course changes of key pathological features of Alzheimer’s disease (AD) and relationship between vascular damage, neuro-inflammation and Aβ in AD model. VEGFR2 expression, vascular number and Aβ levels in cortex and cerebrospinal fluid, cortical and serum inflammatory factor levels, and autonomic activity/memory were analyzed in APP/PS1 mice from 1 to 12-month-old. Transcriptomic analysis of cortical capillaries in one-month-old mice and pathway analysis were performed. Validation of cortical transcriptome data in AD patients from GEO database. Soluble Aβ ₁₋₄₂ oligomers were treated with mouse brain vascular pericytes and endothelial cells. APP/PS1 mice had decreased cortical capillary VEGFR2 expression and vascular dysplasia at 1-month-old, increased endothelial cell apoptosis and decreased capillary density at 3-month-old, increased cortical Aβ ₁₋₄₂ deposition and neuron apoptosis at 6-month-old. APP/PS1 mice showed decreased autonomic activity and increased memory loss at 9-month-old. Cortical capillary transcriptome profiling indicated that a significant energy metabolism deficit was observed at 1-month-old. Increased mRNA expression of vascular-related genes in elderly surviving AD patients. 0.1µM soluble Aβ ₁₋₄₂ oligomers promote angiogenesis, whereas 10µM inhibit it. Cortical capillary dysplasia is a primary contributor to the onset of AD. The accumulation of Aβ in the brain exacerbates vascular hypoplasia by damaging blood vessels, and the interplay between these factors accelerates the progression of AD. Improving vascular functions and energy metabolisms may have potential in delaying or preventing AD.