Function and dysfunction of presenilin.

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Presenilin (PS) genes account for ~90% of mutations causing familial Alzheimer's disease.
• PS proteins are key components of the γ-secretase complex, essential for cleaving receptors like Notch and amyloid precursor protein.
• PS is vital for adult brain functions, including learning, memory, synaptic plasticity, and neuronal survival.

Purpose of the Study:

• To investigate the molecular mechanisms underlying presenilin's essential functions in the adult brain.
• To clarify the role of γ-secretase-dependent activities of PS in memory and neurodegeneration.
• To understand how PS dysfunction contributes to Alzheimer's disease pathogenesis.

Main Methods:

• Genetic analysis using cell type-specific conditional knockout technology in mice.
• Investigating deficits in memory, synaptic function, and neuronal survival in knockout models.
• Comparing deficits in PS and nicastrin knockout mice.

Main Results:

• PS is critical for learning, memory, synaptic function, and age-dependent neuronal survival in the adult brain.
• PS regulates neurotransmitter release, synaptic plasticity, and calcium homeostasis at central synapses.
• PS and nicastrin conditional knockout mice exhibit similar memory deficits and neurodegeneration, suggesting a shared γ-secretase-dependent pathway.

Conclusions:

• γ-secretase-dependent activities of PS are necessary for maintaining memory and neuronal survival.
• Notch receptors, while γ-secretase substrates, may not be the relevant targets for PS in the adult brain's memory functions.
• Despite extensive research, the precise molecular and cellular mechanisms of PS in brain function and disease remain incompletely understood, necessitating further investigation.