title: 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.
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.
authors.affiliation: Département Neurosciences, Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montréal, Québec H3T 1J4, Canada.
authors.forename: Emilie
authors.initials: E
authors.lastname: Trillaud-Doppia
authors.affiliation: Département Neurosciences, Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montréal, Québec H3T 1J4, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Paradis-Isler
authors.affiliation: Département Neurosciences, Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montréal, Québec H3T 1J4, Canada. Electronic address: jannic.boehm@umontreal.ca.
authors.forename: Jannic
authors.initials: J
authors.lastname: Boehm
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000596:Amino Acids / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D003593:Cytoplasm / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D017774:Long-Term Potentiation / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D051381:Rats; D013569:Synapses / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D000596:Amino Acids; D016564:Amyloid beta-Protein Precursor; C498283:Aplp2 protein, rat; D009419:Nerve Tissue Proteins
keywords: APLP2 intracellular domain; APP intracellular domain; Alzheimer disease; Synaptic plasticity