Caspase cleavage of APP contributes to amyloid beta-protein induced synaptic injury
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View abstract on PubMed
Summary
This summary is machine-generated.Amyloid beta (Aβ) causes synaptic dysfunction in Alzheimer's disease (AD) by activating caspases that cleave the amyloid precursor protein (APP), leading to memory loss.
Area Of Science
- Neuroscience
- Molecular Biology
- Cellular Biology
Background
- Amyloid beta (Aβ) is central to Alzheimer's Disease (AD) pathology, initially damaging synapses.
- Caspases are implicated in AD-related synaptic dysfunction and memory loss, but their mechanism is unclear.
- APP cleavage by caspases contributes to Aβ-induced cell death, but its role in synaptic dysfunction is unknown.
Purpose Of The Study
- To investigate the role of caspase-3 and amyloid precursor protein (APP) in Aβ-mediated synaptic dysfunction.
- To elucidate the mechanism of caspase involvement in Alzheimer's Disease.
Main Methods
- Intracellular and extracellular electrophysiology.
- Confocal microscopy of dendritic spines.
- Pharmacological inhibition of caspases and genetic deletion of caspase-3 or APP.
Main Results
- Caspase activity at the intracellular domain of APP is essential for Aβ-induced depression of glutamatergic synapses.
- Inhibition of caspases or absence of caspase-3 prevented Aβ-induced synaptic depression.
- Neurons lacking APP were resistant to Aβ-induced synaptic depression and plasticity inhibition.
- Mutating the caspase cleavage site (664) on APP prevented Aβ-induced synaptic depression and spine loss.
Conclusions
- An APP-dependent pathway exists where caspases contribute to Aβ-induced synaptic depression and spine loss.
- Cleavage of APP by caspases is a key mechanism in Aβ-mediated synaptic damage in Alzheimer's Disease.
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