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Increased AβPP processing in familial Danish dementia patients
Shuji Matsuda1, Robert Tamayev, Luciano D'Adamio
1Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
Journal of Alzheimer'S Disease : JAD
|August 16, 2011
Summary
Familial Danish Dementia (FDD) is caused by a BRI2 mutation. This study shows the mutation leads to toxic amyloid precursor protein (AβPP) metabolites, linking FDD and Alzheimer's disease pathogenesis.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Familial Danish Dementia (FDD) is an autosomal dominant neurodegenerative disease.
- FDD is caused by mutations in the BRI2/ITM2B gene.
- BRI2 interacts with amyloid-β protein precursor (AβPP), inhibiting its processing.
Purpose of the Study:
- To investigate the pathogenic mechanisms of FDD using a novel mouse model.
- To determine the role of AβPP processing in FDD.
- To explore shared pathways between FDD and Alzheimer's disease.
Main Methods:
- Generation of a genetically congruous FDD mouse model (FDDKI).
- Analysis of FDDKI mice and human FDD patient brain samples.
- Biochemical assays to assess AβPP processing and metabolite levels.
- Genetic suppression studies using AβPP haplodeficiency.
Main Results:
- FDDKI mice exhibit loss of Bri2 protein, synaptic plasticity, and memory impairments.
- AβPP/Bri2 complexes are reduced, leading to increased AβPP metabolites in FDDKI mice.
- AβPP haplodeficiency rescues synaptic and memory deficits in FDDKI mice.
- Elevated AβPP metabolites, including Aβ, are observed in human FDD brain samples.
Conclusions:
- The Danish mutation in BRI2 causes loss of Bri2 function, leading to altered AβPP processing.
- Toxic AβPP metabolites are implicated in the neurological deficits of FDD.
- FDD and Alzheimer's disease may share common pathogenic mechanisms involving AβPP metabolism.
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