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

Yan Cai, Xue Mei Zhang, Lauren N. MacKlin, Huaibin Cai, Xue Gang Luo, Salvatore - Oddo, Frank M. Laferla, Robert G. Struble, Gregory M. Rose, Peter R. Patrylo, Xiao Xin Yan

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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 pathology inherent with increased expression of β-secretase (BACE1), the enzyme initiating the amyloidogenic processing of APP. A monoclonal Aβ 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 Aβ 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 Aβ domain and the C-terminal of APP, but not co-labeled by antibodies against the Aβ 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 Aβ antibody IR in transgenic models of AD might relate to a cross-reactivity of putative APP β-carboxyl terminal fragments.

Original languageEnglish (US)
Pages (from-to)160-174
Number of pages15
JournalNeurotoxicity Research
Volume21
Issue number2
DOIs
StatePublished - Feb 2012
Externally publishedYes

Fingerprint

Amyloid beta-Protein Precursor
Amyloid Plaques
Presynaptic Terminals
Pathology
Amyloid
Labeling
Alzheimer Disease
Antibodies
Presenilins
Amyloid Precursor Protein Secretases
Prosencephalon
Animals
Theoretical Models
Monoclonal Antibodies
Axons
Mutation
Molecules
Enzymes
Processing

Keywords

  • Aging
  • Amyloid plaque
  • Axonal pathology
  • Dementia
  • Synaptoplasticity

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

Cite this

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; Zhang, Xue Mei; MacKlin, Lauren N.; Cai, Huaibin; Luo, Xue Gang; Oddo, Salvatore -; Laferla, Frank M.; Struble, Robert G.; Rose, Gregory M.; Patrylo, Peter R.; Yan, Xiao Xin.

In: Neurotoxicity Research, Vol. 21, No. 2, 02.2012, p. 160-174.

Research output: Contribution to journalArticle

Cai, Yan ; Zhang, Xue Mei ; MacKlin, Lauren N. ; Cai, Huaibin ; Luo, Xue Gang ; Oddo, Salvatore - ; Laferla, Frank M. ; Struble, Robert G. ; Rose, Gregory M. ; Patrylo, Peter R. ; Yan, Xiao Xin. / 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. In: Neurotoxicity Research. 2012 ; Vol. 21, No. 2. pp. 160-174.
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