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Accumulation of intraneuronal ?-amyloid 42 peptides is associated with early changes in microtubule-associated protein 2 in neurites and synapses.

ABSTRACT: Pathologic aggregation of ?-amyloid (A?) peptide and the axonal microtubule-associated protein tau protein are hallmarks of Alzheimer's disease (AD). Evidence supports that A? peptide accumulation precedes microtubule-related pathology, although the link between A? and tau remains unclear. We previously provided evidence for early co-localization of A?42 peptides and hyperphosphorylated tau within postsynaptic terminals of CA1 dendrites in the hippocampus of AD transgenic mice. Here, we explore the relation between A? peptide accumulation and the dendritic, microtubule-associated protein 2 (MAP2) in the well-characterized amyloid precursor protein Swedish mutant transgenic mouse (Tg2576). We provide evidence that localized intraneuronal accumulation of A?42 peptides is spatially associated with reductions of MAP2 in dendrites and postsynaptic compartments of Tg2576 mice at early ages. Our data support that reduction in MAP2 begins at sites of A?42 monomer and low molecular weight oligomer (M/LMW) peptide accumulation. Cumulative evidence suggests that accumulation of M/LMW A?42 peptides occurs early, before high molecular weight oligomerization and plaque formation. Since synaptic alteration is the best pathologic correlate of cognitive dysfunction in AD, the spatial association of M/LMW A? peptide accumulation with pathology of MAP2 within neuronal processes and synaptic compartments early in the disease process reinforces the importance of intraneuronal A? accumulation in AD pathogenesis.

SUBMITTER: Takahashi RH

PROVIDER: S-EPMC3553177 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Accumulation of intraneuronal β-amyloid 42 peptides is associated with early changes in microtubule-associated protein 2 in neurites and synapses.

Takahashi Reisuke H RH Capetillo-Zarate Estibaliz E Lin Michael T MT Milner Teresa A TA Gouras Gunnar K GK

PloS one 20130123 1

Pathologic aggregation of β-amyloid (Aβ) peptide and the axonal microtubule-associated protein tau protein are hallmarks of Alzheimer's disease (AD). Evidence supports that Aβ peptide accumulation precedes microtubule-related pathology, although the link between Aβ and tau remains unclear. We previously provided evidence for early co-localization of Aβ42 peptides and hyperphosphorylated tau within postsynaptic terminals of CA1 dendrites in the hippocampus of AD transgenic mice. Here, we explore ...[more]

PMID: 23372648

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Project description:Alzheimer's disease (AD) is characterized by amyloid plaques composed of the β-amyloid (Aβ) peptide surrounded by swollen presynaptic dystrophic neurites consisting of dysfunctional axons and terminals that accumulate the β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) required for Aβ generation. The cellular and molecular mechanisms that govern presynaptic dystrophic neurite formation are unclear, and elucidating these processes may lead to novel AD therapeutic strategies. Previous studies suggest Aβ may disrupt microtubules, which we hypothesize have a critical role in the development of presynaptic dystrophies. To investigate this further, here we have assessed the effects of Aβ, particularly neurotoxic Aβ42, on microtubules during the formation of presynaptic dystrophic neurites in vitro and in vivo. Live-cell imaging of primary neurons revealed that exposure to Aβ42 oligomers caused varicose and beaded neurites with extensive microtubule disruption, and inhibited anterograde and retrograde trafficking. In brain sections from AD patients and the 5XFAD transgenic mouse model of amyloid pathology, dystrophic neurite halos with BACE1 elevation around amyloid plaques exhibited aberrant tubulin accumulations or voids. At the ultrastructural level, peri-plaque dystrophies were strikingly devoid of microtubules and replete with multi-lamellar vesicles resembling autophagic intermediates. Proteins of the microtubule motors, kinesin and dynein, and other neuronal proteins were aberrantly localized in peri-plaque dystrophies. Inactive pro-cathepsin D also accumulated in peri-plaque dystrophies, indicating reduced lysosomal function. Most importantly, BACE1 accumulation in peri-plaque dystrophies caused increased BACE1 cleavage of APP and Aβ generation. Our study supports the hypothesis that Aβ induces microtubule disruption in presynaptic dystrophic neurites that surround plaques, thus impairing axonal transport and leading to accumulation of BACE1 and exacerbation of amyloid pathology in AD.

Dataset Information

Accumulation of intraneuronal ?-amyloid 42 peptides is associated with early changes in microtubule-associated protein 2 in neurites and synapses.

Publications

Accumulation of intraneuronal β-amyloid 42 peptides is associated with early changes in microtubule-associated protein 2 in neurites and synapses.

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