Emerging pathways driving early synaptic pathology in Alzheimer's disease

Area of Science:

• Neuroscience
• Cellular Biology
• Pathophysiology

Background:

• Alzheimer's disease (AD) research faces challenges with failed amyloid-targeting trials.
• A shift is occurring towards understanding early pathogenic mechanisms and synaptic dysfunction.
• Intracellular calcium (Ca2+) signaling disruptions are implicated as early events in AD pathogenesis.

Purpose of the Study:

• To review and integrate new insights into intracellular Ca2+ signaling abnormalities in AD.
• To focus on the role of Ca2+ signaling in driving synaptic deficits and memory loss.
• To identify specific ion channels, organelles, and pathways involved in early AD pathogenesis.

Main Methods:

• Review of recent literature on Ca2+ signaling in AD.
• Integration of findings on endoplasmic reticulum (ER) Ca2+ release channels (IP3R, RyR2).
• Discussion of store-operated calcium entry (SOCE) components (STIM2, TRPC3/6) and lysosomal regulation.

Main Results:

• Excess Ca2+ release from the ER is a consistent finding in AD models and patients.
• Dysregulation of ER Ca2+ channels (RyR2) and SOCE components are implicated.
• Early signaling abnormalities are linked to synaptic pathophysiology and plasticity deficits, particularly short-term plasticity.

Conclusions:

• Intracellular Ca2+ signaling disruptions, especially involving the ER, are critical early events in AD.
• These signaling deficits directly contribute to synaptic dysfunction and memory impairment.
• Targeting these early Ca2+ signaling abnormalities offers a promising avenue for novel AD therapeutics to preserve cognitive function.