The Amyloid Precursor Protein Intracellular Domain Is an Effector Molecule of Metaplasticity.
Human studies and mouse models of Alzheimer's disease suggest that the amyloid precursor protein (APP) can cause changes in synaptic plasticity and is contributing to the memory deficits seen in Alzheimer's disease. While most of these studies attribute these changes to the APP cleavage product Aβ, in recent years it became apparent that the APP intracellular domain (APP-ICD) might play a role in regulating synaptic plasticity.



To separate the effects of APP-ICD on synaptic plasticity from Aβ-dependent effects, we created a chimeric APP in which the Aβ domain is exchanged for its homologous domain from the amyloid precursor-like protein 2.



We show that the expression of this chimeric APP has no effect on basal synaptic transmission or synaptic plasticity. However, a synaptic priming protocol, which in control cells has no effect on synaptic plasticity, leads to a complete block of subsequent long-term potentiation induction and a facilitation of long-term depression induction in neurons expressing chimeric APP. We show that the underlying mechanism for this effect on metaplasticity is caused by caspase cleavage of the APP-ICD and involves activation of ryanodine receptors. Our results shed light on the controversially discussed role of APP-ICD in regulating transcription. Because of the short timespan between synaptic priming and the effect on synaptic plasticity, it is unlikely that APP-ICD-dependent transcription is an underlying mechanism for the regulation of metaplasticity during this time period.



Our finding that the APP-ICD affects metaplasticity provides new insights into the altered regulation of synaptic plasticity during Alzheimer's disease.
Département Neurosciences, Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montréal, Québec, Canada.
Emilie
E
Trillaud-Doppia
Département Neurosciences, Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montréal, Québec, Canada. Electronic address: jannic.boehm@umontreal.ca.
Jannic
J
Boehm
D000544:Alzheimer Disease / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002678:Chimera; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D042541:Intracellular Space / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology*; D051381:Rats; D009435:Synaptic Transmission / Q000502:physiology*
D016564:Amyloid beta-Protein Precursor; C498283:Aplp2 protein, rat; D009419:Nerve Tissue Proteins
Alzheimer’s disease; Amyloid precursor protein; Amyloid precursor protein intracellular domain; Caspase cleavage; Metaplasticity; Synaptic plasticity