Dataset Information

Perinuclear Lamin A and Nucleoplasmic Lamin B2 Characterize Two Types of Hippocampal Neurons through Alzheimer's Disease Progression.

ABSTRACT: BACKGROUND:Recent reports point to a nuclear origin of Alzheimer's disease (AD). Aged postmitotic neurons try to repair their damaged DNA by entering the cell cycle. This aberrant cell cycle re-entry involves chromatin modifications where nuclear Tau and the nuclear lamin are involved. The purpose of this work was to elucidate their participation in the nuclear pathological transformation of neurons at early AD. METHODOLOGY:The study was performed in hippocampal paraffin embedded sections of adult, senile, and AD brains at I-VI Braak stages. We analyzed phospho-Tau, lamins A, B1, B2, and C, nucleophosmin (B23) and the epigenetic marker H4K20me3 by immunohistochemistry. RESULTS:Two neuronal populations were found across AD stages, one is characterized by a significant increase of Lamin A expression, reinforced perinuclear Lamin B2, elevated expression of H4K20me3 and nuclear Tau loss, while neurons with nucleoplasmic Lamin B2 constitute a second population. CONCLUSIONS:The abnormal cell cycle reentry in early AD implies a fundamental neuronal transformation. This implies the reorganization of the nucleo-cytoskeleton through the expression of the highly regulated Lamin A, heterochromatin repression and building of toxic neuronal tangles. This work demonstrates that nuclear Tau and lamin modifications in hippocampal neurons are crucial events in age-related neurodegeneration.

SUBMITTER: Gil L

PROVIDER: S-EPMC7084765 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

Perinuclear Lamin A and Nucleoplasmic Lamin B2 Characterize Two Types of Hippocampal Neurons through Alzheimer's Disease Progression.

Gil Laura L Niño Sandra A SA Chi-Ahumada Erika E Rodríguez-Leyva Ildelfonso I Guerrero Carmen C Rebolledo Ana Belén AB Arias José A JA Jiménez-Capdeville María E ME

International journal of molecular sciences 20200307 5

<h4>Background</h4>Recent reports point to a nuclear origin of Alzheimer's disease (AD). Aged postmitotic neurons try to repair their damaged DNA by entering the cell cycle. This aberrant cell cycle re-entry involves chromatin modifications where nuclear Tau and the nuclear lamin are involved. The purpose of this work was to elucidate their participation in the nuclear pathological transformation of neurons at early AD.<h4>Methodology</h4>The study was performed in hippocampal paraffin embedded ...[more]

PMID: 32155994

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Project description:Current methods for measuring the chronic rates of cognitive decline and degeneration in Alzheimer's disease rely on the sensitivity of longitudinal neuropsychological batteries and clinical neuroimaging, particularly structural magnetic resonance imaging of brain atrophy, either at a global or regional scale. There is particular interest in approaches predictive of future disease progression and clinical outcomes using a single time point. If successful, such approaches could have great impact on differential diagnosis, therapeutic treatment and clinical trial inclusion. Unfortunately, it has proven quite challenging to accurately predict clinical and degeneration progression rates from baseline data. Specifically, a key limitation of the previously proposed approaches for disease progression based on the brain atrophy measures has been the limited incorporation of the knowledge from disease pathology progression models, which suggest a prion-like spread of disease pathology and hence the neurodegeneration. Here, we present a new metric for disease progression rate in Alzheimer that uses only MRI-derived atrophy data yet is able to infer the underlying rate of pathology transmission. This is enabled by imposing a spread process driven by the brain networks using a Network Diffusion Model. We first fit this model to each patient's longitudinal brain atrophy data defined on a brain network structure to estimate a patient-specific rate of pathology diffusion, called the pathology progression rate. Using machine learning algorithms, we then build a baseline data model and tested this rate metric on data from longitudinal Alzheimer's Disease Neuroimaging Initiative study including 810 subjects. Our measure of disease progression differed significantly across diagnostic groups as well as between groups with different genetic risk factors. Remarkably, hierarchical clustering revealed 3 distinct clusters based on CSF profiles with >90% accuracy. These pathological clusters exhibit progressive atrophy and clinical impairments that correspond to the proposed rate measure. We demonstrate that a subject's degeneration speed can be best predicted from baseline neuroimaging volumetrics and fluid biomarkers for subjects in the middle of their degenerative course, which may be a practical, inexpensive screening tool for future prognostic applications.

Dataset Information

Perinuclear Lamin A and Nucleoplasmic Lamin B2 Characterize Two Types of Hippocampal Neurons through Alzheimer's Disease Progression.

Publications

Perinuclear Lamin A and Nucleoplasmic Lamin B2 Characterize Two Types of Hippocampal Neurons through Alzheimer's Disease Progression.

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