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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Faller EM, Villeneuve TS, Brown DL (2009) MAP1a associated light chain 3 increases microtubule stability by suppressing microtubule dynamics. Mol Cell Neurosci 41(1):85–93
Fifre A, Sponne I, Koziel V, Kriem B, Yen Potin FT, Bihain BE, Olivier JL, Oster T, Pillot T (2006) Microtubule-associated protein MAP1A, MAP1B, and MAP2 proteolysis during soluble amyloid beta-peptide-induced neuronal apoptosis. Synergistic involvement of calpain and caspase-3. J Biol Chem 281(1):229–240
Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297(5580):353–356
Hsia AY, Masliah E, McConlogue L, Yu GQ, Tatsuno G, Hu K, Kholodenko D, Malenka RC, Nicoll RA, Mucke L (1999) Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models. Proc Natl Acad Sci USA 96(6):3228–3233
Jin M, Shepardson N, Yang T, Chen G, Walsh D, Selkoe DJ (2011) Soluble amyloid {beta}-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc Natl Acad Sci USA 108(14):5819–5824
Klein WL (2006) Synaptic targeting by A beta oligomers (ADDLS) as a basis for memory loss in early Alzheimer’s disease. Alzheimers Dement 2(1):43–55
Lacor PN, Buniel MC, Chang L, Fernandez SJ, Gong Y, Viola KL, Lambert MP, Velasco PT, Bigio EH, Finch CE, Krafft GA, Klein WL (2004) Synaptic targeting by Alzheimer’s-related amyloid beta oligomers. J Neurosci 24(45):10191–10200
Masliah E, Mallory M, Alford M, DeTeresa R, Hansen LA, McKeel DW Jr, Morris JC (2001) Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease. Neurology 56(1):127–129
Michaelis ML, Ansar S, Chen Y, Reiff ER, Seyb KI, Himes RH, Audus KL, Georg GI (2005) {beta}-Amyloid-induced neurodegeneration and protection by structurally diverse microtubule-stabilizing agents. J Pharmacol Exp Ther 312(2):659–668
Nieto A, Correas I, Montejo de Garcini E, Avila J (1988) A modified form of microtubule-associated tau protein is the main component of paired helical filaments. Biochem Biophys Res Commun 154(2):660–667
Ono K, Condron MM, Teplow DB (2009) Structure–neurotoxicity relationships of amyloid beta-protein oligomers. Proc Natl Acad Sci USA 106(35):14745–14750
Ruiz-Munoz AM, Nieto-Escamez FA, Aznar S, Colomina MT, Sanchez-Santed F (2011) Cognitive and histological disturbances after chlorpyrifos exposure and chronic Abeta(1–42) infusions in Wistar rats. Neurotoxicology 32(6):836–844
Schoenfeld TA, McKerracher L, Obar R, Vallee RB (1989) MAP 1A and MAP 1B are structurally related microtubule associated proteins with distinct developmental patterns in the CNS. J Neurosci 9(5):1712–1730
Shankar GM, Leissring MA, Adame A, Sun X, Spooner E, Masliah E, Selkoe DJ, Lemere CA, Walsh DM (2009) Biochemical and immunohistochemical analysis of an Alzheimer’s disease mouse model reveals the presence of multiple cerebral Abeta assembly forms throughout life. Neurobiol Dis 36(2):293–302
Sponne I, Fifre A, Drouet B, Klein C, Koziel V, Pincon-Raymond M, Olivier JL, Chambaz J, Pillot T (2003) Apoptotic neuronal cell death induced by the non-fibrillar amyloid-beta peptide proceeds through an early reactive oxygen species-dependent cytoskeleton perturbation. J Biol Chem 278(5):3437–3445
Szebenyi G, Bollati F, Bisbal M, Sheridan S, Faas L, Wray R, Haferkamp S, Nguyen S, Caceres A, Brady ST (2005) Activity-driven dendritic remodeling requires microtubule-associated protein 1A. Curr Biol 15(20):1820–1826
Tong L, Balazs R, Thornton PL, Cotman CW (2004) Beta-amyloid peptide at sublethal concentrations downregulates brain-derived neurotrophic factor functions in cultured cortical neurons. J Neurosci 24(30):6799–6809
Walsh DM, Selkoe DJ (2004) Deciphering the molecular basis of memory failure in Alzheimer’s disease. Neuron 44(1):181–193
Wasling P, Daborg J, Riebe I, Andersson M, Portelius E, Blennow K, Hanse E, Zetterberg H (2009) Synaptic retrogenesis and amyloid-beta in Alzheimer’s disease. J Alzheimers Dis 16(1):1–14
Wei Z, Song MS, MacTavish D, Jhamandas JH, Kar S (2008) Role of calpain and caspase in beta-amyloid-induced cell death in rat primary septal cultured neurons. Neuropharmacology 54(4):721–733
Wimo A, Winblad B, Aguero-Torres H, von Strauss E (2003) The magnitude of dementia occurrence in the world. Alzheimer Dis Assoc Disord 17(2):63–67
Zempel H, Thies E, Mandelkow E, Mandelkow EM (2010) Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci 30(36):11938–11950
Acknowledgments
This study was supported by the Lundbeck Foundation.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Clemmensen, C., Aznar, S., Knudsen, G.M. et al. The Microtubule-Associated Protein 1A (MAP1A) is an Early Molecular Target of Soluble Aβ-Peptide. Cell Mol Neurobiol 32, 561–566 (2012). https://doi.org/10.1007/s10571-011-9796-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-011-9796-9