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; 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.
Cai
Yan
Y
Department of Anatomy and Neurobiology, Central South University Xiangya Medical School, Changsha, Hunan, China.
Xiong
Kun
K
Zhang
Xue-Mei
XM
Cai
Huaibin
H
Luo
Xue-Gang
XG
Feng
Jia-Chun
JC
Clough
Richard W
RW
Struble
Robert G
RG
Patrylo
Peter R
PR
Chu
Yaping
Y
Kordower
Jeffrey H
JH
Yan
Xiao-Xin
XX
D000375:Aging / Q000473:pathology*; D000544:Alzheimer Disease / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D002540:Cerebral Cortex / Q000201:enzymology* / Q000473:pathology*; D003576:Electron Transport Complex IV; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D008970:Molecular Weight; D009252:NADPH Dehydrogenase; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D011180:Postmortem Changes; D017729:Presynaptic Terminals / Q000378:metabolism / Q000473:pathology; D016622:Silver Staining / Q000379:methods; D018709:Statistics, Nonparametric; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; D016875:tau Proteins; D009252:NADPH Dehydrogenase; D003576:Electron Transport Complex IV; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human