Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive neuronal cell loss. Recently, dysregulation of intracellular Ca2+ homeostasis has been suggested as a common proximal cause of neural dysfunction in AD. Here, we investigated (1) the pathogenic role of destabilization of ryanodine receptor (RyR2) in endoplasmic reticulum (ER) upon development of AD phenotypes in AppNL-G-F mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic), and (2) the therapeutic effect of enhanced calmodulin (CaM) binding to RyR2. In the neuronal cells from AppNL-G-F mice, CaM dissociation from RyR2 was associated with AD-related phenotypes, i.e. Aβ accumulation, TAU phosphorylation, ER stress, neuronal cell loss, and cognitive dysfunction. Surprisingly, either genetic (by V3599K substitution in RyR2) or pharmacological (by dantrolene) enhancement of CaM binding to RyR2 reversed almost completely the aforementioned AD-related phenotypes, except for Aβ accumulation. Thus, destabilization of RyR2 due to CaM dissociation is most likely an early and fundamental pathogenic mechanism involved in the development of AD. The discovery that neuronal cell loss can be fully prevented simply by stabilizing RyR2 sheds new light on the treatment of AD.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive neuronal cell loss
We investigated whether enhancement of CaM binding to RyR2 influences development of AD, using AppNL-G-F mice and RyR2V3599K/V3599K mice (RyR2V3599K)
To examine whether stabilization of RyR2 through enhanced CaM binding is critical for AD pathogenesis, we generated AppNL-G-F/RyR2V3599K double homozygous mice (AppNL-G-F/RyR2 V3599K mice), and evaluated how the AD phenotype is modified (Supplementary Fig. 1)
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive neuronal cell loss. In the neuronal cells from AppNL-G-F mice, CaM dissociation from RyR2 was associated with AD-related phenotypes, i.e. Aβ accumulation, TAU phosphorylation, ER stress, neuronal cell loss, and cognitive dysfunction. Increasing evidence suggests that Ca2+ signaling dysregulation mediates accumulation of the unfolded proteins, which triggers endoplasmic reticulum (ER) stress, in turn resulting in synaptic dysfunction in AD4–7 It is unclear how Ca2+ dysregulation is involved in ER stress and Aβ in neuronal cells. Neuronal cell density in a slice of Cornu Ammonis (CA) 1 and the dentate gyrus (DG) of the hippocampus (3 μm thickness) were measured by counting all NeuN stained cells devided CA 1 or DG area, and values for individual mice are plotted together with mean ± SEM. To the zipped state, and restored normal CaM binding to RyR2, thereby inhibiting Ca2+ leakage in either CPVT-associated RyR2R2474S/+ mouse model[9], tachycardia-induced canine heart failure model[15], or pressureoverload induced mouse heart failure model[18]
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