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In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
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17q21.31 duplication causes prominent tau-related dementia with increased MAPT expression
K Le Guennec1,2, O Quenez1,2,3, G Nicolas1,2,3,4
1Inserm, U1079, faculté de médecine, Rouen University, IRIB, Normandy University, Rouen, France.
Molecular Psychiatry
|December 14, 2016
Summary
Rare copy number variations, specifically a 17q21.31 microduplication involving the MAPT gene, are linked to early-onset dementia. This genetic factor causes tauopathy, mimicking Alzheimer's disease clinically but lacking amyloid plaques.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Alzheimer's disease (AD) pathogenesis is complex, with rare genetic variations potentially playing a role.
- Understanding genetic underpinnings of early-onset dementia is crucial for diagnosis and treatment.
Purpose of the Study:
- To investigate the role of rare copy number variations (CNVs) in early-onset Alzheimer's disease.
- To identify specific genetic rearrangements associated with AD phenotypes.
Main Methods:
- Case-control study utilizing whole-exome sequencing data from early-onset AD cases and controls.
- Analysis of copy number variations, gene expression, clinical data, neuroimaging, and cerebrospinal fluid biomarkers.
- Neuropathological examination of a confirmed case.
Main Results:
- A recurrent 17q21.31 microduplication, encompassing CRHR1, MAPT, STH, and KANSL1 genes, was identified in early-onset AD cases but not controls.
- Increased MAPT gene dosage resulted in elevated MAPT messenger RNA expression.
- MAPT duplication carriers presented with clinical, neuroimaging, and biomarker profiles consistent with AD, but negative amyloid PET scans.
- Neuropathology confirmed MAPT duplication causes tauopathy without amyloid-β deposits, presenting as a novel dementia entity.
Conclusions:
- The 17q21.31 microduplication is the genetic basis for a novel early-onset dementia entity characterized by prominent tauopathy.
- This condition mimics Alzheimer's disease clinically but is distinguished by the absence of amyloid pathology.
- This tauopathy entity may explain a subset of AD cases with negative amyloid PET imaging.
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