Synaptic and Sub-Synaptic Localization of Amyloid-ß Protein Precursor in the Rat Hippocampus.

Journal of Alzheimer's disease : JAD

PubMedID: 24531160

Rodrigues DI, Gutierres J, Pliássova A, Oliveira CR, Cunha RA, Agostinho P. Synaptic and Sub-Synaptic Localization of Amyloid-ß Protein Precursor in the Rat Hippocampus. J Alzheimers Dis. 2014;.
Amyloid-ß protein precursor (AßPP) is a large transmembrane protein highly expressed in the central nervous system and cleavage of it can produce amyloid-ß peptides (Aß) involved in synaptic dysfunction and loss associated with cognitive impairment in Alzheimer's disease (AD). Surprisingly, little is known about the synaptic and sub-synaptic distribution of AßPP in different types of nerve terminals. We used total, synaptic, sub-synaptic, and astrocytic membrane preparations obtained from the hippocampus of adult rats to define the localization of AßPP, using two different antibodies against different AßPP epitopes. Western blot analysis revealed that AßPP was not significantly enriched in synaptosomal as compared to total membranes. Within synapses, AßPP immunoreactivity was more abundant in pre- (60 ± 4%) than post- (30 ± 5%) or extra-synaptic fractions (10 ± 2%). Immunocytochemical analysis of purified nerve terminals indicated that AßPP was more frequently associated with glutamatergic (present in 31 ± 4% of glutamatergic terminals) rather than with GABAergic (16 ± 3%) or cholinergic terminals (4 ± 1%, n = 4). We also observed a general lack of co-localization of AßPP and GFAP immunoreactivities in the hippocampus of sections of adult rat brain, albeit we could detect the presence of AßPP in gliosomes (vesicular specializations of astrocytic membranes), suggesting that AßPP has a heterogeneous localization restricted to certain regions of astrocytes. These results provide the first direct demonstration that AßPP is mostly distributed among glutamatergic rather than GABAergic or cholinergic terminals of the adult rat hippocampus, in remarkable agreement with the particular susceptibility to dysfunction and degeneration of glutamatergic synapses in early AD.