Abstract
Massive deposition of amyloid β peptides (Aβ) as senile plaques (SP) characterizes the brain pathology of Alzheimer’s disease (AD). SPs exhibit a variety of morphologies, although little is known about the SP components that determine their morphology. Collagenous Alzheimer amyloid plaque component (CLAC) is one of the major non-Aβ proteinaceous components of SP amyloid in AD brains. Here we show that overexpression of CLAC precursor (CLAC-P) in the brains of APP transgenic mice results in a significant remodeling of amyloid pathology, i.e., reduction in diffuse-type amyloid plaques and an increase in compact plaques laden with thioflavin S-positive amyloid cores. In vivo microdialysis revealed a significant decrease in Aβ in the brain interstitial fluid of CLAC-P/APP double transgenic mice compared with APP transgenic mice. These findings implicate CLAC in the compaction of Aβ in amyloid plaques and the brain dynamics of Aβ.
Highlights
Senile plaques (SPs) are the pathological hallmark lesions in the brains of patients with Alzheimer’s disease (AD), of which the major building blocks are amyloid fibrils composed of amyloid-β peptides (Aβ) [17]
We examined the expression levels of human Collagenous Alzheimer amyloid plaque component (CLAC)-P protein in the brains of F2 generation derived from eight F0 founders by immunoblotting and immunohistochemistry, and obtained two high-expressor lines, of which we used the line #74 throughout the study
We previously showed that CLAC precursor (CLAC-P) is cleaved by furin convertase after the domain 107KIRIAR112 to release its extracellular domain as a secreted form of CLACP, which co-deposits with Aβ in AD brains as CLAC [18]
Summary
Senile plaques (SPs) are the pathological hallmark lesions in the brains of patients with Alzheimer’s disease (AD), of which the major building blocks are amyloid fibrils composed of amyloid-β peptides (Aβ) [17]. Swollen dystrophic neurites are associated with the primitive and typical plaques, which are interpreted as signatures of local amyloid toxicity [31, 42]. Some reports have suggested the correlation between the ThSpositive mature plaques and neurotoxicity and synaptic dysfunction in the brains of AD patients and APP transgenic (tg) mice, implicating the role of mature plaques in the pathological progression of AD [43, 52]. In contrast to the “mature” plaques, “diffuse” plaques composed of amorphous Aβ deposits that are negative for ThS and lack the association of dystrophic neurites [58].
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