β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade

Abstract

The brain noradrenergic system is critical for normal cognition and is affected at early stages in Alzheimer’s disease (AD). Here, we reveal a previously unappreciated direct role of norepinephrine signaling in connecting β-amyloid (Aβ) and tau, two key pathological components of AD pathogenesis. Our results show that Aβ oligomers bind to an allosteric site on α2A adrenergic receptor (α2AAR) to redirect norepinephrine-elicited signaling to glycogen synthase kinase 3β (GSK3β) activation and tau hyperphosphorylation. This norepinephrine-dependent mechanism sensitizes pathological GSK3β/tau activation in response to nanomolar accumulations of extracellular Aβ, which is 50- to 100-fold lower than the amount required to activate GSK3β by Aβ alone. The significance of our findings is supported by in vivo evidence in two mouse models, human tissue sample analysis, and longitudinal clinical data. Our study provides translational insights into mechanisms underlying Aβ proteotoxicity, which might have strong implications for the interpretation of Aβ clearance trial results and future drug design and for understanding the selective vulnerability of noradrenergic neurons in AD.

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

“…Very recent studies shed light on the possible role of adrenergic receptors: AβO can bind to an allosteric site of the alpha2A receptor. This binding changes norepinephrine signaling and activates glycogen synthase kinase 3β (GSK3β), thereby triggering tau hyperphosphorylation [120].…”

Identification of amyloid beta oligomers in locus coeruleus (LC) neurons of Alzheimer’s patients and their impact on LC oxidative stress, inhibitory neurotransmitter receptors and neuronal excitability

“…Furthermore, AβO promote the uptake of tau fibril seeds potentiating intracellular aggregation (Shin et al 2019a) and mediate neurite degeneration (Jin et al 2011). Mechanistic insights into this AβO-tau interaction arise from intriguing new data that demonstrate the involvement of NA, and α2 A adrenergic receptors (α2 A ARs) in mediating tau hyperphosphorylation and Alzheimer’s-related pathology in human and animal samples (Zhang et al 2020). Given the significant degree of LC axonal collaterals that provide negative feedback modulation of LC neuronal activity via α2 A ARs (Aghajanian et al 1977) (Cedarbaum and Aghajanian 1976), dysregulation of LC hyperexcitability, in combination with locally produced AβO, could set in motion the early levels of tau tangle formation distinctive in this brain region.…”

Naphthalene monoimide derivative ameliorates amyloid burden and cognitive decline in a transgenic mouse model of Alzheimer’s disease

“…As discussed (vide supra), the chronic Aβ plaques deposition induced dendritic and axonal atrophy in the AD brain contributing to the loss of mature neurons and neuronal circuit disruption (10,11,48). The soluble Aβ aggregation species interact with synaptic receptors (NMDA and AMPA) at the synaptic cleft hampering the neuronal signaling cascade, memory formation and cognitive functions (12,14,49). Double transgenic APP/PS1 AD mice show AD phenotypes viz., accumulation of chronic Aβ plaques, memory impairments, cognitive decline and neuronal loss with age (4,50).…”