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Alzheimer's disease (AD) is the most common dementia-causing disorder in the elderly; it may be related to multiple risk factors, and is characterized pathologically by cerebral hypometabolism, paravascular β-amyloid peptide (Aβ) plaques, neuritic dystrophy, and intra-neuronal aggregation of phosphorylated tau. To explore potential pathogenic links among some of these lesions, we examined β-secretase-1 (BACE1) alterations 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 protein 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 for 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 markers (GABAergic, glutamatergic, cholinergic, or catecholaminergic). Importantly, these BACE1-labeled dystrophic axons resided near to or in direct contact with blood vessels. These findings suggest that plaque formation in AD or normal aged primates relates to a multisystem axonal pathogenesis that occurs in partnership with a potential vascular or metabolic deficit. The data provide a mechanistic explanation for why senile plaques are present preferentially near the cerebral vasculature. [ABSTRACT FROM AUTHOR]

Cerebral hypometabolism and amyloid accumulation are principal neuropathological manifestations of Alzheimer’s disease (AD). Whether and how brain/neuronal activity might modulate certain pathological processes of AD are interesting topics of recent clinical and basic research in the field, and may be of potential medical relevance in regard to both the disease etiology and intervention. Using the Tg2576 transgenic mouse model of AD, this study characterized a promotive effect of neuronal hypoactivity associated with functional deprivation on amyloid plaque pathogenesis in the olfactory pathway. Unilateral naris-occlusion caused β-secretase-1 (BACE1) elevation in neuronal terminals in the deprived relative to the non-deprived bulb and piriform cortex in young adult mice. In parallel with the overall age-related plaque development in the forebrain, locally increased BACE1 immunoreactivity co-occurred with amyloid deposition first in the piriform cortex then within the bulb, more prominent on the deprived relative to the non-deprived side. Biochemical analyses confirmed elevated BACE1 protein levels, enzymatic activity and products in the deprived relative to non-deprived bulbs. Plaque-associated BACE1 immunoreactivity in the bulb and piriform cortex was localized preferentially to swollen/sprouting glutamatergic axonal terminals, with Aβ immunoreactivity occurring inside as well as around these terminals. Together, these findings suggest that functional deprivation or neuronal hypoactivity facilitates amyloid plaque formation in the forebrain in a transgenic model of AD, which operates synergistically with age effect. The data also implicate an intrinsic association of amyloid accumulation and plaque formation with progressive axonal pathology. [ABSTRACT FROM AUTHOR]

The presence of neuritic plaques is a pathological hallmark of Alzheimer’s disease (AD). However, the origin of extracellular β-amyloid peptide (Aβ) deposits and the process of plaque development remain poorly understood. The present study attempted to explore plaque pathogenesis by localizing β-secretase-1 (BACE1) elevation relative to Aβ accumulation and synaptic/neuritic alterations in the forebrain, using transgenic mice harboring familial AD (FAD) mutations (5XFAD and 2XFAD) as models. In animals with fully developed plaque pathology, locally elevated BACE1 immunoreactivity (IR) coexisted with compact-like Aβ deposition, with BACE1 IR occurring selectively in dystrophic axons of various neuronal phenotypes or origins (GABAergic, glutamatergic, cholinergic or catecholaminergic). Prior to plaque onset, localized BACE1/Aβ IR occurred at swollen presynaptic terminals and fine axonal processes. These BACE1/Aβ-containing axonal elements appeared to undergo a continuing process of sprouting/swelling and dystrophy, during which extracellular Aβ IR emerged and accumulated in surrounding extracellular space. These data suggest that BACE1 elevation and associated Aβ overproduction inside the sprouting/dystrophic axonal terminals coincide with the onset and accumulation of extracellular amyloid deposition during the development of neuritic plaques in transgenic models of AD. Our findings appear to be in harmony with an early hypothesis that axonal pathogenesis plays a key or leading role in plaque formation. [ABSTRACT FROM AUTHOR]