Abstract
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 the relation between Aβ 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 Aβ42 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 Aβ42 monomer and low molecular weight oligomer (M/LMW) peptide accumulation. Cumulative evidence suggests that accumulation of M/LMW Aβ42 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 Aβ peptide accumulation with pathology of MAP2 within neuronal processes and synaptic compartments early in the disease process reinforces the importance of intraneuronal Aβ accumulation in AD pathogenesis.
Highlights
Alzheimer disease (AD) neuropathology is characterized by aggregation of the b-amyloid (Ab) peptide in plaques and the hyperphosphorylated tau protein in neurofibrillary tangles (NFTs) [1]
We previously demonstrated in brains of amyloid precursor protein (APP) Swedish mutant transgenic mice (Tg2576) that intraneuronal Ab42 peptides accumulate with aging in endosomes, in particular multivesicular bodies (MVBs), in distal processes and synaptic compartments [13] prior to Ab plaques
We previously reported that immunoreactivity for the high molecular weight (HMW) Ab42 oligomer-specific antibody M16 is absent in brains of wildtype mice at all ages, and in brains of Tg2576 mice until just prior to plaque formation, where it consistently was associated with structural pathology within neurites [36]
Summary
Alzheimer disease (AD) neuropathology is characterized by aggregation of the b-amyloid (Ab) peptide in plaques and the hyperphosphorylated tau protein in neurofibrillary tangles (NFTs) [1]. We previously demonstrated in brains of amyloid precursor protein (APP) Swedish mutant transgenic mice (Tg2576) that intraneuronal Ab42 peptides accumulate with aging in endosomes, in particular multivesicular bodies (MVBs), in distal processes and synaptic compartments [13] prior to Ab plaques. Prior to Ab plaques, marked accumulation and oligomerization of Ab42 peptides within processes and synaptic compartments was associated with subcellular pathology, including a reduced or absent microtubular network [13,22]. The accumulation of Ab peptides and associated structural and functional alterations in MAPs within synapses are significant, because synaptic alterations are the best pathologic correlate of cognitive dysfunction [26]
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