Caspase cleavage of APP contributes to amyloid beta-protein induced synaptic injury

Increasing evidence suggests that amyloid beta (Aβ) lies at the center of Alzheimer's Disease (AD) pathology and that synapses are the initial site of damage by Aβ. Recent studies have also indicated a role for caspases in AD-related synaptic dysfunction and memory loss, but the mechanism(s) through which the caspases act remains elusive. Previous studies in cell culture indicate that cleavage of a caspase site on the intracellular domain of the amyloid precursor protein (APP) protein contributes to Aβ-induced cell death. However, the role of this cleavage event in synaptic dysfunction has not been established.

Through a combination of intracellular and extracellular electrophysiological methods and confocal microscopy of dendritic spines, we examined the involvement of caspase-3 and amyloid-precursor protein in Aβ-mediated synaptic dysfunction.

Here, we provide evidence that caspase activity at the intracellular domain of APP is required for acute Aβ-induced depression of glutamatergic synapses. We find that local elevation of Aβ levels through over-expression of the C-terminal fragment of APP (C99) failed to depress synapses if caspases were inhibited pharmacologically or in tissue lacking caspase-3. To demonstrate a link between these findings to APP, we found that Aβ failed to depress synaptic transmission or inhibit synaptic plasticity in neurons lacking APP. To specifically test the role of caspase cleavage of the intracellular domain of APP, we introduced a mutation that inhibits caspase cleavage at site 664 to the C99 construct; this construct produced Aβ but failed to elicit Aβ-induced synaptic depression or spine loss, and reduced caspase-3 activity.

Taken together, these results suggest an APP-dependent pathway in which caspases contribute to Aβ-induced synaptic depression and spine loss via cleavage of APP.