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Neurobiol Dis. 2016 Jul;91:94-104. doi: 10.1016/j.nbd.2016.02.016. Epub 2016 Feb 24.

A single amino acid difference between the intracellular domains of amyloid precursor protein and amyloid-like precursor protein 2 enables induction of synaptic depression and block of long-term potentiation.

Author information

1
Département Neurosciences, Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montréal, Québec H3T 1J4, Canada.
2
Département Neurosciences, Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montréal, Québec H3T 1J4, Canada. Electronic address: jannic.boehm@umontreal.ca.

Abstract

Alzheimer disease (AD) is initially characterized as a disease of the synapse that affects synaptic transmission and synaptic plasticity. While amyloid-beta and tau have been traditionally implicated in causing AD, recent studies suggest that other factors, such as the intracellular domain of the amyloid-precursor protein (APP-ICD), can also play a role in the development of AD. Here, we show that the expression of APP-ICD induces synaptic depression, while the intracellular domain of its homolog amyloid-like precursor protein 2 (APLP2-ICD) does not. We are able to show that this effect by APP-ICD is due to a single alanine vs. proline difference between APP-ICD and APLP2-ICD. The alanine in APP-ICD and the proline in APLP2-ICD lie directly behind a conserved caspase cleavage site. Inhibition of caspase cleavage of APP-ICD prevents the induction of synaptic depression. Finally, we show that the expression of APP-ICD increases and facilitates long-term depression and blocks induction of long-term potentiation. The block in long-term potentiation can be overcome by mutating the aforementioned alanine in APP-ICD to the proline of APLP2. Based on our results, we propose the emergence of a new APP critical domain for the regulation of synaptic plasticity and in consequence for the development of AD.

KEYWORDS:

APLP2 intracellular domain; APP intracellular domain; Alzheimer disease; Synaptic plasticity

PMID:
26921470
DOI:
10.1016/j.nbd.2016.02.016
[Indexed for MEDLINE]

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