Work

A Unifying Mechanism for Synaptic Amyloid β Toxicity β Adrenergic Potentiation of the Ca 2+ Channel CaV1.2 by Amyloid β

Year: 2026

Type: preprint

Abstract: ABSTRACT Amyloid β peptides (Aβ) trigger Alzheimer’s disease (AD) but how has remained elusive. Aβ stimulates the β 2 adrenergic receptor (β 2 AR), which forms a unique signaling complex with the L-type Ca 2+ channel (LTCC) Ca V 1.2. LTCCs have been implicated in the etiology of dementia and AD. We show that Aβ acutely potentiates Ca V 1.2 via the β 2 AR, which triggers postsynaptic recruitment of Ca 2+ permeable (CP) AMPARs in hippocampal cultures and impairs LTP in hippocampal slices within minutes. The long-term consequence is a loss of postsynaptic structure of glutamatergic synapses and neurotoxicity. Disrupting this signaling cascade with highly specific tools prevented all of these effects, unifying a number of currently divergent findings on Aβ synaptotoxicity including dysregulation of AMPARs and synaptic plasticity. TEASER Amyloid β peptide is the primary pathological agent in Alzheimer’s disease. It affects the nanoscale structure and function of glutamatergic synapses. The molecular mechanisms are largely unknown except for identification of several binding proteins including the β 2 adrenergic receptor. We show that this binding potently (EC 50 <100 nM) augments Ca 2+ influx through the L-type Ca channel Ca V 1.2. This effect leads to improper recruitment of Ca 2+ -permeable glutamate receptors to postsynaptic sites (EC 50 <100 nM), synaptic dysfunction and ultimately neuronal death. This work identifies an essential mechanism in amyloid β neurotoxicity and explains many of the observed postsynaptic alterations. Highlights Immediate effects of Aβ-induced stimulation of β 2 AR on Cav1.2: Aβ induces phosphorylation of Cav1.2 on S1928 by PKA Aβ augments Cav1.2 activity via β 2 AR-induced S1928 phosphorylation within seconds Aβ-induced β 2 AR - Cav1.2 signaling has the following synaptotoxic effects. Aβ induces postsynaptic accumulation of Ca-permeable AMPARs via β 2 AR - Cav1.2 signaling within 20 min Aβ impairs long-term potentiation (LTP) via β 2 AR - Cav1.2 signaling Aβ impairs postsynaptic structure and neuronal viability over 24 h Potency of Aβ in all the above effects is very high (100 nM Aβ is saturating!) All effects are prevented in S1928A KI mice and acute displaces β 2 AR from Cav1.2 with tat-Pep 1923

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.04.25.720803