Lessons from a Rare Familial Dementia: Amyloid and Beyond

Area of Science:

• Neurodegenerative Diseases
• Molecular Biology
• Genetics

Background:

• Familial British dementia (FBD) is a rare inherited neurodegenerative disorder.
• Alzheimer's disease (AD) is the most common late-life neurological condition.
• Both FBD and AD involve protein oligomers and aberrant amyloid precursor protein (APP) processing.

Purpose of the Study:

• To review similarities between FBD and AD.
• To explore the roles of protein oligomers and APP processing in FBD.
• To propose a "two-hit mechanism" for FBD pathogenesis.

Main Methods:

• Review of FBD symptoms, pathology, and genetics.
• Examination of BRI2 protein biology and FBD mouse models.
• Analysis of protein oligomer formation and APP processing in FBD and AD.

Main Results:

• FBD involves deposition of amyloid peptide ABri, distinct from AD's amyloid-beta (Aβ).
• Studies suggest both toxic gain of function (ABri oligomers) and loss of function (BRI2) contribute to FBD.
• Mutant BRI2 interacts with and alters APP processing, contributing to FBD pathology.

Conclusions:

• A "two-hit mechanism" involving toxic ABri oligomers and altered APP processing better explains FBD.
• Lessons from FBD suggest AD pathology also involves aberrant aggregation and altered APP processing.
• Further study of ABri oligomers and APP metabolites in FBD may illuminate AD pathogenesis.