These authors contributed equally to this work.
β-Secretase-1 elevation in transgenic mouse models of Alzheimer’s disease is associated with synaptic/axonal pathology and amyloidogenesis: implications for neuritic plaque development
Version of Record online: 10 DEC 2009
© The Authors (2009). Journal Compilation © Federation of European Neuroscience Societies and Blackwell Publishing Ltd
European Journal of Neuroscience
Volume 30, Issue 12, pages 2271–2283, December 2009
How to Cite
Zhang, X.-M., Cai, Y., Xiong, K., Cai, H., Luo, X.-G., Feng, J.-C., Clough, R. W., Struble, R. G., Patrylo, P. R. and Yan, X.-X. (2009), β-Secretase-1 elevation in transgenic mouse models of Alzheimer’s disease is associated with synaptic/axonal pathology and amyloidogenesis: implications for neuritic plaque development. European Journal of Neuroscience, 30: 2271–2283. doi: 10.1111/j.1460-9568.2009.07017.x
- Issue online: 15 DEC 2009
- Version of Record online: 10 DEC 2009
- Received 16 August 2009, accepted 6 October 2009
- dystrophic neurite;
- senile plaques
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.