β-Secretase-1 elevation in aged monkey and Alzheimer’s disease human cerebral cortex occurs around the vasculature in partnership with multisystem axon terminal pathogenesis and β-amyloid accumulation

Alzheimer's disease (AD) is the most common dementia-causing disorder in the elderly, which may relate to multiple risk factors and is pathologically featured by cerebral hypometabolism, paravascular β-amyloid (Aβ) plaques, neuritic dystrophy and intra-neuronal aggregation of phosphorylated-tau. To explore potential pathogenic link among some of these lesions, we examined β-secretase-1 (BACE1) alteration relative to Aβ deposition, neuritic pathology and vascular organization in aged monkey and AD human cerebral cortex. Western blot analyses detected increased levels of BACE1 proteins and β-site-cleavage amyloid precursor protein C-terminal fragments in plaque-bearing human and monkey cortex relative to controls. In immunohistochemistry, locally elevated BACE1 immunoreactivity (IR) occurred in AD but not in control human cortex, with a trend of increased overall density among cases with greater plaque pathology. In double labeling preparations, BACE1 IR colocalized with immunolabeling for Aβ but not for phosphorylated tau. In perfusion-fixed monkey cortex, locally increased BACE1 IR co-existed with intra-axonal and extracellular Aβ IR among virtually all neuritic plaques ranging from primitive to typical cored forms. This BACE1 labeling localized to swollen/sprouting axon terminals that might co-express one or another neuronal phenotype marker (GABAergic, glutamatergic, cholinergic or catecholaminergic). Importantly, these BACE1-labeled dystrophic axons resided near or in direct contact with blood vessels. These finds implicate that plaque formation in AD or normal aging primates relate to a multisystem axonal pathogenesis that occurs in partnership with potential vascular or metabolic deficit. The data provide a tangible mechanistic explanation as to why senile plaques are present preferentially near cerebral vasculature.