Genetic Mapping of APP and Amyloid-β Biology Modulation by Trisomy 21

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Down syndrome (DS) is linked to early-onset Alzheimer's disease (AD), with trisomy 21 increasing amyloid precursor protein (APP) gene copies.
• The exact genetic mechanisms driving AD pathogenesis in DS, beyond APP duplication, remain incompletely understood.

Purpose of the Study:

• To investigate how genes on chromosome 21, other than APP, influence amyloid-beta (Aβ) accumulation in the brain.
• To identify specific genetic regions and candidate genes on chromosome 21 that modulate AD-related pathology in DS mouse models.

Main Methods:

• Utilized next-generation mouse models of DS (Tc1, Dp3Tyb, Dp(10)2Yey, Dp(17)3Yey) and an Aβ accumulation knockin model (AppNL-F).
• Analyzed Aβ levels in male and female mice with trisomy for chromosome 21 genes.
• Employed a mapping approach to pinpoint a subregion of chromosome 21 responsible for modulating Aβ levels and investigated candidate genes DYRK1A and BACE2.

Main Results:

• Trisomy of chromosome 21 genes, independent of APP copy number, partially ameliorates Aβ accumulation in the brain.
• Identified a specific subregion on chromosome 21 containing gene(s) that decrease Aβ levels.
• DYRK1A and BACE2 were investigated as potential candidates influencing Aβ pathology.

Conclusions:

• Extra copies of chromosome 21 genes, beyond APP, can modulate APP/Aβ metabolism in the brain under physiological conditions.
• This finding provides mechanistic insight into AD development in DS and explains the typically later onset of dementia compared to familial AD caused by APP triplication.