title: Synaptic dysfunction in Alzheimer's disease.
abstract: Generation of amyloid peptide (Aβ) is at the beginning of a cascade that leads to Alzheimer's disease (AD). Amyloid precursor protein (APP), as well as β- and γ-secretases, is the principal player involved in Aβ production, while α-secretase cleavage on APP prevents Aβ deposition. Recent studies suggested that soluble assembly states of Aβ peptides can cause cognitive problems by disrupting synaptic function in the absence of significant neurodegeneration. Therefore, current research investigates the relative importance of these various soluble Aβ assemblies in causing synaptic dysfunction and cognitive deficits. Several Aβ oligomers targets and cellular mechanisms responsible of Aβ-induced synaptic failure have been identified. The first and most important mechanism impugns a toxic gain of function for Aβ which results due to self-association and attainment of new structures capable of novel interactions that lead to impaired plasticity. Other scenarios predicate that Aβ has a normal physiological role. On the one hand, insufficient Aβ could lead to a loss of normal function, whereas excess Aβ may precipitate dysfunction. How this occurs and which the main target/s is/are for the synaptic action of Aβ remains to be fully understood and would certainly represent one of the main challenges to future AD research.
authors.affiliation: Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. elena.marcello@unimi.it
authors.forename: Elena
authors.initials: E
authors.lastname: Marcello
authors.forename: Roberta
authors.initials: R
authors.lastname: Epis
authors.forename: Claudia
authors.initials: C
authors.lastname: Saraceno
authors.forename: Monica
authors.initials: M
authors.lastname: Di Luca
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D003071:Cognition; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D051379:Mice; D009473:Neuronal Plasticity; D058105:Polymerization; D011485:Protein Binding; D051381:Rats; D011950:Receptors, Cholinergic / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D011950:Receptors, Cholinergic; D017470:Receptors, Glutamate; D018698:Glutamic Acid; D053829:Amyloid Precursor Protein Secretases; D000109:Acetylcholine