Beta-secretase-1 elevation in transgenic mouse models of Alzheimer's disease is associated with synaptic/axonal pathology and amyloidogenesis: implications for neuritic plaque development.
The presence of neuritic plaques is a pathological hallmark of Alzheimer's disease (AD). However, the origin of extracellular beta-amyloid peptide (Abeta) deposits and the process of plaque development remain poorly understood. The present study attempted to explore plaque pathogenesis by localizing beta-secretase-1 (BACE1) elevation relative to Abeta 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 Abeta 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/Abeta IR occurred at swollen presynaptic terminals and fine axonal processes. These BACE1/Abeta-containing axonal elements appeared to undergo a continuing process of sprouting/swelling and dystrophy, during which extracellular Abeta IR emerged and accumulated in surrounding extracellular space. These data suggest that BACE1 elevation and associated Abeta 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.
Zhang
Xue-Mei
XM
Department of Anatomy, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
Cai
Yan
Y
Xiong
Kun
K
Cai
Huaibin
H
Luo
Xue-Gang
XG
Feng
Jia-Chun
JC
Clough
Richard W
RW
Struble
Robert G
RG
Patrylo
Peter R
PR
Yan
Xiao-Xin
XX
D000375:Aging; D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D001369:Axons / Q000473:pathology / Q000502:physiology*; D005110:Extracellular Space / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000473:pathology / Q000502:physiology; D058225:Plaque, Amyloid / Q000473:pathology / Q000502:physiology*; D053764:Presenilin-1 / Q000235:genetics; D017729:Presynaptic Terminals / Q000473:pathology / Q000502:physiology; D016548:Prosencephalon / Q000473:pathology / Q000503:physiopathology*; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000235:genetics; D013569:Synapses / Q000473:pathology / Q000502:physiology*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D053764:Presenilin-1; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse