The Association of Amyloid-β Protein Precursor With α- and β-Secretases in Mouse Cerebral Cortex Synapses Is Altered in Early Alzheimer’s Disease
Mol Neurobiol. 2015-10-26; 53(8): 5710-5721
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Pliássova A(1)(2), Lopes JP(1), Lemos C(1), Oliveira CR(1)(2), Cunha RA(1)(2), Agostinho P(3)(4).
(1)CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.
(2)FMUC-Faculty of Medicine, University of Coimbra, 3004-504, Coimbra, Portugal.
(3)CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal. .
(4)FMUC-Faculty of Medicine, University of Coimbra, 3004-504, Coimbra, Portugal. .
Amyloid-β peptides (Aβ), the proposed triggers of synaptic dysfunction in early
Alzheimer’s disease (AD), derive from the endoproteolytic cleavage of amyloid-β
precursor protein (APP) by β-secretases (BACE1), whereas APP cleavage by
α-secretases (ADAM10) abrogates Aβ formation. We now mapped the synaptic
localization of APP, ADAM10, and BACE1 in the mouse cerebral cortex. All three
proteins were present in cortical synapses and subsynaptic fractionation revealed
that APP was located mainly in the pre-synaptic active zone (53 %) and in the
post-synaptic density (37 %), whereas ADAM10 was enriched in the post-synaptic
density (61 %) and BACE1 was concentrated in extra-synaptic regions (72 %).
Immunocytochemistry analysis further showed that APP and BACE1 were co-localized
in about 30 % of both glutamatergic and GABAergic terminals, whereas few
terminals were endowed with ADAM10. This distribution is modified in a mouse
model of early AD based on Aβ1-42-intracerebroventricular injection, where the
synaptic levels of APP and ADAM10 increased by 30 %, whereas BACE1 levels were
reduced. This suggests that, in early AD, there are compensatory mechanisms to
avoid Aβ overload in cortical synapses favoring the non-amyloidogenic processing