The Association of Amyloid-β Protein Precursor With α- and β-Secretases in Mouse Cerebral Cortex Synapses Is Altered in Early Alzheimer's Disease.
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 of APP.
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.|FMUC-Faculty of Medicine, University of Coimbra, 3004-504, Coimbra, Portugal.
Anna
A
Pliássova
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.
João P
JP
Lopes
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.
Cristina
C
Lemos
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.|FMUC-Faculty of Medicine, University of Coimbra, 3004-504, Coimbra, Portugal.
Catarina R
CR
Oliveira
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.|FMUC-Faculty of Medicine, University of Coimbra, 3004-504, Coimbra, Portugal.
Rodrigo A
RA
Cunha
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal. pmgagostinho@gmail.com.|FMUC-Faculty of Medicine, University of Coimbra, 3004-504, Coimbra, Portugal. pmgagostinho@gmail.com.
Paula
P
Agostinho
D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism*; D004195:Disease Models, Animal; D008297:Male; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D013569:Synapses / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases
ADAM10; APP; Alzheimer’s disease; BACE1; Synapses