基礎講座 電気泳動(Electrophoresis)

The neuropathological hallmarks of Alzheimer disease (AD) include “positive” lesions such as amyloid plaques and cerebral amyloid angiopathy, neurofibrillary tangles, and glial responses, and “negative” lesions such as neuronal and synaptic loss. Despite their inherently cross-sectional nature, postmortem studies have enabled the staging of the progression of both amyloid and tangle pathologies, and, consequently, the development of diagnostic criteria that are now used worldwide. In addition, clinicopathological correlation studies have been crucial to generate hypotheses about the pathophysiology of the disease, by establishing that there is a continuum between “normal” aging and AD dementia, and that the amyloid plaque build-up occurs primarily before the onset of cognitive deficits, while neurofibrillary tangles, neuron loss, and particularly synaptic loss, parallel the progression of cognitive decline. Importantly, these cross-sectional neuropathological data have been largely validated by longitudinal in vivo studies using modern imaging biomarkers such as amyloid PET and volumetric MRI.

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Neuropathological Alterations in Alzheimer Disease

Degeneration and regeneration of the nervous system

The journal of neuroscience : the official journal of the Society for Neuroscience.

50 Years of Image Analysis

The cause of neuronal degeneration in Alzheimer's disease.

The morphological phenotype of β-amyloid plaques and associated neuritic changes in Alzheimer’s disease

We have investigated alterations in myelin associated with Aβ plaques, a major pathological hallmark of Alzheimer’s disease (AD), in human tissue and relevant transgenic mice models. Using quantitative morphological techniques, we determined that fibrillar Aβ pathology in the grey matter of the neocortex was associated with focal demyelination in human presenilin-1 familial, sporadic and preclinical AD cases, as well as in two mouse transgenic models of AD, compared with age-matched control tissue. This demyelination was most pronounced at the core of Aβ plaques. Furthermore, we found a focal loss of oligodendrocytes in sporadic and preclinical AD cases associated with Aβ plaque cores. In human and transgenic mice alike, plaque-free neocortical regions showed no significant demyelination or oligodendrocyte loss compared with controls. Dystrophic neurites associated with the plaques were also demyelinated. We suggest that such plaque-associated focal demyelination of the cortical grey matter might impair cortical processing, and may also be associated with aberrant axonal sprouting that underlies dystrophic neurite formation.

Focal demyelination in Alzheimer’s disease and transgenic mouse models

A yeast two-hybrid library was screened using the cytoplasmic domain of the axonal cell adhesion molecule L1 to identify binding partners that may be involved in the regulation of L1 function. The intracellular domain of L1 bound to ezrin, a member of the ezrin, radixin, and moesin (ERM) family of membrane-cytoskeleton linking proteins, at a site overlapping that for AP2, a clathrin adaptor. Binding of bacterial fusion proteins confirmed this interaction. To determine whether ERM proteins interact with L1 in vivo, extracellular antibodies to L1 were used to force cluster the protein on cultured hippocampal neurons and PC12 cells, which were then immunolabeled for ERM proteins. Confocal analysis revealed a precise pattern of codistribution between ERMs and L1 clusters in axons and PC12 neurites, whereas ERMs in dendrites and spectrin labeling remained evenly distributed. Transfection of hippocampal neurons grown on an L1 substrate with a dominant negative ERM construct resulted in extensive and abnormal elaboration of membrane protrusions and an increase in axon branching, highlighting the importance of the ERM-actin interaction in axon development. Together, our data indicate that L1 binds directly to members of the ERM family and suggest this association may coordinate aspects of axonal morphogenesis.

https://rupress.org/jcb/article-pdf/157/7/1105/1303487/jcb15771105.pdf

Tracey C. Dickson

Papers

The cause of neuronal degeneration in Alzheimer's disease.

The morphological phenotype of β-amyloid plaques and associated neuritic changes in Alzheimer’s disease

Focal demyelination in Alzheimer’s disease and transgenic mouse models

Functional binding interaction identified between the axonal CAM L1 and members of the ERM family

Neurochemical diversity of dystrophic neurites in the early and late stages of Alzheimer's disease.