Soluble Aβ Promotes Wild-Type Tau PathologyIn Vivo

Abstract

Growing evidence suggests that soluble Aβ species can drive Alzheimer disease (AD) pathogenesis by inducing a cascade of events including tau hyperphosphorylation, proteasome impairment and synaptic dysfunction. However, these studies have relied largely on in vitro approaches to examine the role of soluble Aβ in AD. In particular, it remains unknown whether soluble Aβ oligomers can facilitate the development of human wild-type tau pathology in vivo. To address this question, we developed a novel transgenic model that expresses low levels of APP with the Arctic familial AD mutation to enhance soluble Aβ oligomer formation in conjunction with wild-type human tau. Using a genetic approach, we show that reduction of β-site APP cleaving enzyme (BACE) in these “ArcTau” mice decreases soluble Aβ oligomers, rescues cognition, and more importantly also reduces tau accumulation and phosphorylation. Notably, BACE reduction decreases the postsynaptic mislocalization of tau in ArcTau mice, and reduces the association between NMDA receptors and PSD-95. These studies provide critical in vivo evidence for a strong mechanistic link between soluble Aβ, wild-type tau and synaptic pathology.

Synergistic effects of amyloid-beta and wild-type human tau on dendritic spine loss in a floxed double transgenic model of Alzheimer's disease

“…Interestingly, despite the cognitive deficits observed at 12 months in this model, there are no differences in synaptic markers PSD-95 and synaptophysin with age (Figure 1H–I). Because the triad of Aβ, tau, and the protein kinase Fyn has been implicated in synaptoxocity, we also examined levels of Fyn and its substrate NR2B (Ittner et al 2010, Chabrier et al 2012). Levels of the NMDAR subunits NR2B are significantly elevated at 12 months of age compared to young 3 month hAPP SL mice, while a trend toward increased phosphorylated NR2B at tyrosine-1472 is observed at 18 months of age (Figure 1I).…”

“…Full-length human tau 2N/4R cDNA was used previously in our models (Chabrier et al, 2012) and was originally a gift from Dr. Michael Vitek. hAPP SL and hTau constructs were subcloned into the Thy1.2 expression cassette (Caroni, 1997) using a homologous recombination approach (Clonetech, In-Fusion).…”

Interactions between Aβ oligomers and presynaptic cholinergic signaling: Age-dependent effects on attentional capacities

“…Therefore, development of drugs targeting Aβ oligomers may hold promise to restore presynaptic cholinergic transmission and decline in attentional capacities in early AD. As abnormal tau phosphorylation is also induced by Aβ oligomers [70-72], and this pathological feature is also linked to cholinergic atrophy during the later stages of AD [73], therapeutic approaches that detoxify oligomeric Aβ may also offer tremendous potential to slow down the disease progression and cholinergic dysfunction with age.…”

Accelerated tau pathology with synaptic and neuronal loss in a novel triple transgenic mouse model of Alzheimer's disease

“…Downregulation of the b-site APP cleaving enzyme BACE1 reduces the amount of soluble Ab oligomers leading to reduced tau accumulation and phosphorylation (Chabrier et al, 2012).…”