The microtubule-associated protein 1A (MAP1A) is an early molecular target of soluble Aβ-peptide

TY - JOUR

T1 - The microtubule-associated protein 1A (MAP1A) is an early molecular target of soluble Aβ-peptide

AU - Clemmensen, C

AU - Aznar, S

AU - Knudsen, G M

AU - Klein, A B

AU - Klein, Anders Bue

PY - 2012/5

Y1 - 2012/5

N2 - 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.

AB - 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.

KW - Alzheimer Disease

KW - Amyloid beta-Peptides

KW - Animals

KW - Female

KW - Memory, Episodic

KW - Microtubule-Associated Proteins

KW - Nerve Degeneration

KW - Neurons

KW - Pregnancy

KW - Primary Cell Culture

KW - Rats

KW - Rats, Sprague-Dawley

KW - Solubility

U2 - 10.1007/s10571-011-9796-9

DO - 10.1007/s10571-011-9796-9

M3 - Journal article

C2 - 22252785

SN - 0272-4340

VL - 32

SP - 561

EP - 566

JO - Cellular & Molecular Neurobiology

JF - Cellular & Molecular Neurobiology

IS - 4

ER -