Ryanodine receptors: physiological function and deregulation in Alzheimer disease

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• Alzheimer disease (AD) is linked to disrupted endoplasmic reticulum (ER) calcium (Ca2+) homeostasis.
• Alterations in Ryanodine Receptor (RyR) expression and function are observed in human AD brains and AD models.

Purpose of the Study:

• To review evidence on the role of RyR in AD pathogenesis.
• To discuss mechanisms of RyR alteration in AD.
• To explore RyR modulators as potential AD therapeutics.

Main Methods:

• Review of existing literature on RyR and AD.
• Analysis of studies on familial AD mutations and transgenic AD models.
• Examination of data on RyR's impact on beta-amyloid precursor protein (βAPP) processing, neuronal death, synaptic function, and cognition.

Main Results:

• RyR alterations are associated with βAPP processing, Aβ peptide production, neuronal death, and cognitive deficits in AD.
• RyR exhibits a complex dual role, potentially being both protective and pathogenic in AD.
• Studies in AD mouse models show RyR blockade reduces Aβ, stabilizes synapses, and improves learning/memory.

Conclusions:

• RyR dysfunction is implicated in AD pathogenesis, influencing key disease hallmarks.
• RyR modulators represent a promising therapeutic avenue for Alzheimer disease.
• Targeting RyR could offer a novel strategy to slow or halt AD progression.