In:
Brain and Behavior, Wiley, Vol. 2, No. 3 ( 2012-05), p. 270-282
Abstract:
β‐Secretase, BACE1 is a neuron‐specific membrane‐associated protease that cleaves amyloid precursor protein (APP) to generate β‐amyloid protein (Aβ). BACE1 is partially localized in lipid rafts. We investigated whether lipid raft localization of BACE1 affects Aβ production in neurons using a palmitoylation‐deficient mutant and further analyzed the relationship between palmitoylation of BACE1 and its shedding and dimerization. We initially confirmed that BACE1 is mainly palmitoylated at four C‐terminal cysteine residues in stably transfected neuroblastoma cells. We found that raft localization of mutant BACE1 lacking the palmitoylation modification was markedly reduced in comparison to wild‐type BACE1 in neuroblastoma cells as well as rat primary cortical neurons expressing BACE1 via recombinant adenoviruses. In primary neurons, expression of wild‐type and mutant BACE1 enhanced production of Aβ from endogenous or overexpressed APP to similar extents with the β‐C‐terminal fragment (β‐CTF) of APP mainly distributed in nonraft fractions. Similarly, β‐CTF was recovered mainly in nonraft fractions of neurons expressing Swedish mutant APP only. These results show that raft association of BACE1 does not influence β‐cleavage of APP and Aβ production in neurons, and support the view that BACE1 cleaves APP mainly in nonraft domains. Thus, we propose a model of neuronal Aβ generation involving mobilization of β‐CTF from nonraft to raft domains. Additionally, we obtained data indicating that palmitoylation plays a role in BACE1 shedding but not dimerization.
Type of Medium:
Online Resource
ISSN:
2162-3279
,
2162-3279
Language:
English
Publisher:
Wiley
Publication Date:
2012
detail.hit.zdb_id:
2623587-0
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