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

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 don’t. 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.

Prolonged Running, not Fluoxetine Treatment, Increases Neurogenesis, but does not Alter Neuropathology, in the 3xTg Mouse Model of Alzheimer’s Disease

“…Moreover, we used an antibody directed against N-terminal Aβ (IBL #18584). Previously, in the hybrid 3xTg strain at ages of 2, 14, and 20 months, a monoclonal antibody directed at amino acids 1–5 of the N-terminal Aβ variant (3D6, Elan, South San Francisco, CA, USA) has been used to visualize Aβ deposits (Cai et al 2012). These authors found that 3D6 labels Aβ deposits across the cortex and pyramidal layer in 2-month-old animals, where it appears as perisomatic puncta or granules.…”

Cellular prion protein modulates β-amyloid deposition in aged APP/PS1 transgenic mice

“…No differences in APP levels were observed at any time point in any of the genotypes. bsecretase has been implicated in amyloid production and plaque formation (Cai et al, 2011), and its activity is directly related to Ab load Ho et al, 2005). Several authors have proposed that b-secretase cleavage of APP by BACE1 is inhibited by PrP c , and that the absence of PrP c promotes an increase in Ab production, supporting a relationship between b-secretase and PrP c (Kellett and Hooper, 2009;Parkin et al, 2007).…”

Axonal Transport Defects in Alzheimer’s Disease

“…Although there are numerous studies regarding AD, the cause and progression of AD are still not well understood. Synaptic dysfunction and axonal pathology that take place prior to the deposition of amyloid plaques and tau aggregation in transgenic AD animal models [1] and the significant reduction in myelination observed within brain areas affected in AD [2] suggest that axonal dysfunction and degeneration represent important components in AD. The maintenance and function of axons and synapses rely on the AT, which keeps axons and nerve terminals supplied with proteins, lipids, and energy, and clears recycled or misfolded proteins to avoid the formation of toxic aggregates.…”