title: The microtubule-associated protein 1A (MAP1A) is an early molecular target of soluble Aβ-peptide.
abstract: A progressive accumulation of amyloid β-protein (Aβ) is widely recognized as a pathological hallmark of Alzheimer's disease (AD). Substantial progress has been made toward understanding the neurodegenerative cascade initiated by small soluble species of Aβ and recent evidence supports the notion that microtubule rearrangements may be proximate to neuritic degeneration and deficits in episodic declarative memory. Here, we examined primary cortical neurons for changes in markers associated with synaptic function following exposure to sublethal concentrations of non-aggregated Aβ-peptide. This data show that soluble Aβ species at a sublethal concentration induce degradation of the microtubule-associated protein 1A (MAP1A) without concurrently affecting dendritic marker MAP2 and/or the pre-synaptic marker synaptophysin. In addition, MAP1A was found to highly co-localize with the postsynaptic density-95 (PSD-95) protein, proposing that microtubule perturbations might be central for the Aβ-induced neuronal dysfunctions as PSD-95 plays a key role in synaptic plasticity. In conclusion, this study suggests that disruption of MAP1A could be a very early manifestation of Aβ-mediated synaptic dysfunction-one that presages the clinical onset of AD by years. Moreover, our data support the notion of microtubule-stabilizing agents as effective AD drugs.
authors.affiliation: Center for Integrated Molecular Brain Imaging (CIMBI), Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
authors.forename: C
authors.initials: C
authors.lastname: Clemmensen
authors.forename: S
authors.initials: S
authors.lastname: Aznar
authors.forename: G M
authors.initials: GM
authors.lastname: Knudsen
authors.forename: A B
authors.initials: AB
authors.lastname: Klein
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D005260:Female; D061212:Memory, Episodic; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D011247:Pregnancy; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
chemical_list: D016229:Amyloid beta-Peptides; C490546:Map1a protein, rat; D008869:Microtubule-Associated Proteins