Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Genetics

Background:

• Alzheimer's disease (AD) is a leading cause of dementia, characterized by brain amyloid plaques and neurofibrillary tangles.
• Familial AD (fAD) is linked to genetic mutations affecting amyloid precursor protein (APP) processing, notably in PSEN1 and PSEN2 genes.

Purpose of the Study:

• To investigate the functional impact of two novel PSEN1 variants (p.T119I and p.R358P) identified in early-onset AD patients.
• To evaluate the role of these PSEN1 variants in APP processing and their potential contribution to fAD.

Main Methods:

• Developed a cellular model using CRISPR/Cas9-generated PSEN1 Knock-Out (KO) HEK293T cells.
• Assessed the Aβ 42 /Aβ 40 ratio, a key AD biomarker, in cells transfected with wild-type PSEN1, novel PSEN1 variants, or a known pathogenic PSEN1 mutation.

Main Results:

• The PSEN1 R358P variant significantly increased the Aβ 42 /Aβ 40 ratio, primarily due to reduced Aβ 40 levels.
• The PSEN1 T119I variant showed a trend towards increasing this ratio.
• The known pathogenic PSEN1 A246E mutation also elevated the Aβ 42 /Aβ 40 ratio.

Conclusions:

• The PSEN1 R358P variant shows potential pathogenicity in fAD.
• This pathogenic role appears independent of a co-occurring SORL1 variant found in the patient.