APP/Aβ structural diversity and Alzheimer's disease pathogenesis

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• The amyloid cascade hypothesis implicates amyloid-beta (Aβ) in Alzheimer's disease (AD) dementia.
• Current AD therapies target monomeric and oligomeric Aβ 1-40 and 1-42.
• Alternative APP processing and posttranslational modifications (PTMs) generate diverse Aβ species.

Purpose of the Study:

• To propose that amplified production and modification of Aβ species accelerate AD neurodegeneration.
• To catalog Aβ PTMs, including isoAsp, pyroglutamate, and Met35 oxidation.
• To investigate how these modifications impact Aβ structure, toxicity, and propagation.

Main Methods:

• Literature survey to catalog Aβ PTMs.
• Analysis of the structural and biophysical properties of modified Aβ species.
• Correlation of modified Aβ species with AD pathology and dementia.

Main Results:

• Identified Aβ PTMs, such as isoAsp, pyroglutamate, and Met35 oxidation, are prevalent in AD.
• These modifications alter Aβ structure, increasing toxicity, aggregation, and resistance to degradation.
• Modified Aβ species exhibit prion-like seeding and propagation, contributing to neurodegeneration.

Conclusions:

• Accumulation of modified Aβ species is intrinsically linked to dementia progression in AD.
• Specific Aβ conformations and PTMs drive neurotoxicity and brain-wide amyloid transmission.
• Systematic examination of Aβ PTMs can yield essential biomarkers for AD staging and therapeutic development.