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Beta secretase localization, amyloid deposition and aberrant synaptic and neuritic sprouting in transgenic mouse Alzheimer models: a role for BACE1 in synaptic remodeling and plaque formation?
Author(s) -
Clough Rich W,
Zhang XueMei,
Cai Huaibin,
Ebersole Jeremy,
Yan Cai,
Struble Robert G,
Patrylo Peter R,
Yan XiaoXin
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.834.6
Subject(s) - senile plaques , synaptophysin , neurite , genetically modified mouse , bace1 as , pathology , neuroscience , amyloid precursor protein , sprouting , amyloid (mycology) , amyloid precursor protein secretase , transgene , p3 peptide , biology , microbiology and biotechnology , chemistry , alzheimer's disease , immunohistochemistry , medicine , disease , biochemistry , botany , gene , in vitro
Amyloid plaques are a pathological hallmark of Alzheimer's disease (AD). Diffuse plaques consist largely of deposited beta amyloid peptides (Ab). Neuritic plaques also contain dystrophic neurites and reactive gliosis in the vicinity of Ab deposits. The origin of Ab deposits and process of plaque development remain unknown. We hypothesize that Ab deposition begins at sites of aberrant neuroplasticity. BACE immunolabeling, Ab accumulation and neuritic alterations were analyzed in transgenic mouse models of AD (with single and combined human APP, PS1 and tau mutations: Tg2576, 2XFAD, 5XFAD and 3XTg). BACE1 immunoreactivity occurred in neuritic‐like plaques in all strains of transgenics. BACE1‐labeled elements in the plaques co‐expressed synaptophysin and growth associated protein‐43 (GAP‐43), suggestive of sprouting axons. Of note, perisomatic BACE1 and Ab labeling coexisted with synaptophysin around principal neurons in younger transgenics. These findings suggest: 1) BACE1 elevation coincides with Ab overload in neurons, synaptic terminals and plaques in transgenic AD models; (2) axonal misrouting or aberrant sprouting may be an early and crucial event of plaque pathogenesis; (3) BACE1‐mediated Ab overproduction and release from sprouting or remodeling neurites play an active role in plaque formation. Supported by SIUSOM and the Illinois Department of Public Health.

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