Abstract
β-Site amyloid precursor protein (APP) cleaving enzyme-1 (BACE1) is the β-secretase that initiates Aβ production in Alzheimer’s disease (AD). BACE1 levels are increased in AD, which could contribute to pathogenesis, yet the mechanism of BACE1 elevation is unclear. Furthermore, the normal function of BACE1 is poorly understood. We localized BACE1 in the brain at both the light and electron microscopic levels to gain insight into normal and pathophysiologic roles of BACE1 in health and AD, respectively. Our findings provide the first ultrastructural evidence that BACE1 localizes to vesicles (likely endosomes) in normal hippocampal mossy fiber terminals of both non-transgenic and APP transgenic (5XFAD) mouse brains. In some instances, BACE1-positive vesicles were located near active zones, implying a function for BACE1 at the synapse. In addition, BACE1 accumulated in swollen dystrophic autophagosome-poor presynaptic terminals surrounding amyloid plaques in 5XFAD cortex and hippocampus. Importantly, accumulations of BACE1 and APP co-localized in presynaptic dystrophies, implying increased BACE1 processing of APP in peri-plaque regions. In primary cortical neuron cultures, treatment with the lysosomal protease inhibitor leupeptin caused BACE1 levels to increase; however, exposure of neurons to the autophagy inducer trehalose did not reduce BACE1 levels. This suggests that BACE1 is degraded by lysosomes but not by autophagy. Our results imply that BACE1 elevation in AD could be linked to decreased lysosomal degradation of BACE1 within dystrophic presynaptic terminals. Elevated BACE1 and APP levels in plaque-associated presynaptic dystrophies could increase local peri-plaque Aβ generation and accelerate amyloid plaque growth in AD.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-013-1152-3) contains supplementary material, which is available to authorized users.
Highlights
Alzheimer’s disease (AD) is characterized by the presence of neurofibrillary tangles and cerebral amyloid plaques composed of the 40–42 amino acid β-amyloid peptide (Aβ; reviewed in Sisodia and Hyslop [98])
Initial beta-site APP cleaving enzyme 1 (BACE1) immunohistochemistry results using BACE–Cat1 suggested that the highest levels of BACE1 in the brain were located in stratum lucidum of the CA3 hippocampal subregion [121]
Our data and other published reports [57, 93] indicate that a large proportion of endogenous BACE1 in the brain is localized within presynaptic neuronal terminals, but little if any BACE1 is present in postsynaptic areas other than the soma
Summary
Alzheimer’s disease (AD) is characterized by the presence of neurofibrillary tangles and cerebral amyloid plaques composed of the 40–42 amino acid β-amyloid peptide (Aβ; reviewed in Sisodia and Hyslop [98]). BACE1-null mice display complex neurological phenotypes, including growth retardation [24], memory deficits [57, 77, 78], hypomyelination [37, 113], seizures [33, 39, 50], axon guidance defects [13, 32, 85], and schizophrenia-like behaviors [91] These BACE1−/− phenotypes likely reflect the functions of a diverse array of BACE1 substrates that include Golgi-localized membranebound α2,6-sialyltransferase [49], P-selectin glycoprotein ligand-1 [63], APP and the APP homolog proteins APLP1 and APLP2 [25, 61, 79], low density lipoprotein receptorrelated protein [108], the voltage-gated sodium channel β2 subunit (Navβ2) [46, 47, 114], neuregulin-1 (NRG1) [37, 113], neuregulin-3 (NRG3) [36], and Close Homolog of L1 (CHL1) [32, 55, 123], among others [55, 123]. Additional as yet unknown BACE1 substrates are likely to exist and their identification will provide further insight into the biological functions of BACE1
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
