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BACE1 elevation is involved in amyloid plaque development in the triple transgenic model of Alzheimer's disease: differential A? antibody labeling of early-onset axon terminal pathology.

ABSTRACT: ?-amyloid precursor protein (APP) and presenilins mutations cause early-onset familial Alzheimer's disease (FAD). Some FAD-based mouse models produce amyloid plaques, others do not. ?-Amyloid (A?) deposition can manifest as compact and diffuse plaques; it is unclear why the same A? molecules aggregate in different patterns. Is there a basic cellular process governing A? plaque pathogenesis? We showed in some FAD mouse models that compact plaque formation is associated with a progressive axonal pathology inherent with increased expression of ?-secretase (BACE1), the enzyme initiating the amyloidogenic processing of APP. A monoclonal A? antibody, 3D6, visualized distinct axon terminal labeling before plaque onset. The present study was set to understand BACE1 and axonal changes relative to diffuse plaque development and to further characterize the novel axonal A? antibody immunoreactivity (IR), using triple transgenic AD (3xTg-AD) mice as experimental model. Diffuse-like plaques existed in the forebrain in aged transgenics and were regionally associated with increased BACE1 labeled swollen/sprouting axon terminals. Increased BACE1/3D6 IR at axon terminals occurred in young animals before plaque onset. These axonal elements were also co-labeled by other antibodies targeting the N-terminal and mid-region of A? domain and the C-terminal of APP, but not co-labeled by antibodies against the A? C-terminal and APP N-terminal. The results suggest that amyloidogenic axonal pathology precedes diffuse plaque formation in the 3xTg-AD mice, and that the early-onset axonal A? antibody IR in transgenic models of AD might relate to a cross-reactivity of putative APP ?-carboxyl terminal fragments.

SUBMITTER: Cai Y

PROVIDER: S-EPMC3227764 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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BACE1 elevation is involved in amyloid plaque development in the triple transgenic model of Alzheimer's disease: differential Aβ antibody labeling of early-onset axon terminal pathology.

Cai Yan Y Zhang Xue-Mei XM Macklin Lauren N LN Cai Huaibin H Luo Xue-Gang XG Oddo Salvatore S Laferla Frank M FM Struble Robert G RG Rose Gregory M GM Patrylo Peter R PR Yan Xiao-Xin XX

Neurotoxicity research 20110702 2

β-amyloid precursor protein (APP) and presenilins mutations cause early-onset familial Alzheimer's disease (FAD). Some FAD-based mouse models produce amyloid plaques, others do not. β-Amyloid (Aβ) deposition can manifest as compact and diffuse plaques; it is unclear why the same Aβ molecules aggregate in different patterns. Is there a basic cellular process governing Aβ plaque pathogenesis? We showed in some FAD mouse models that compact plaque formation is associated with a progressive axonal p ...[more]

PMID: 21725719

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Project description:Backgroundβ-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting enzyme in the production of amyloid beta (Aβ), the toxic peptide that accumulates in the brains of Alzheimer's disease (AD) patients. Our previous studies have shown that the clathrin adaptor Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3) plays a key role in the trafficking of BACE1 to lysosomes, where it is normally degraded. GGA3 depletion results in BACE1 stabilization both in vitro and in vivo. Moreover, levels of GGA3 are reduced and inversely related to BACE1 levels in post-mortem brains of AD patients.MethodIn order to assess the effect of GGA3 deletion on AD-like phenotypes, we crossed GGA3 -/- mice with 5XFAD mice. BACE1-mediated processing of APP and the cell adhesion molecule L1 like protein (CHL1) was measured as well as levels of Aβ42 and amyloid burden.ResultsIn 5XFAD mice, we found that hippocampal and cortical levels of GGA3 decreased while BACE1 levels increased with age, similar to what is observed in human AD brains. GGA3 deletion prevented age-dependent elevation of BACE1 in GGA3KO;5XFAD mice. We also found that GGA3 deletion resulted in increased hippocampal levels of Aβ42 and amyloid burden in 5XFAD mice at 12 months of age. While levels of BACE1 did not change with age and gender in GGAKO;5XFAD mice, amyloid precursor protein (APP) levels increased with age and were higher in female mice. Moreover, elevation of APP was associated with a decreased BACE1-mediated processing of CHL1 not only in 12 months old 5XFAD mice but also in human brains from subjects affected by Down syndrome, most likely due to substrate competition.ConclusionThis study demonstrates that GGA3 depletion is a leading candidate mechanism underlying elevation of BACE1 in AD. Furthermore, our findings suggest that BACE1 inhibition could exacerbate mechanism-based side effects in conditions associated with APP elevation (e.g. Down syndrome) owing to impairment of BACE1-mediated processing of CHL1. Therefore, therapeutic approaches aimed to restore GGA3 function and to prevent the down stream effects of its depletion (e.g. BACE1 elevation) represent an attractive alternative to BACE inhibition for the prevention/treatment of AD.

Dataset Information

BACE1 elevation is involved in amyloid plaque development in the triple transgenic model of Alzheimer's disease: differential A? antibody labeling of early-onset axon terminal pathology.

Publications

BACE1 elevation is involved in amyloid plaque development in the triple transgenic model of Alzheimer's disease: differential Aβ antibody labeling of early-onset axon terminal pathology.

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