The Amygdala as a Locus of Pathologic Misfolding in Neurodegenerative Diseases

Area of Science:

• Neurodegenerative diseases
• Neuropathology
• Brain anatomy and function

Background:

• The amygdala accumulates misfolded proteins in common neurodegenerative diseases.
• Misfolding of one protein often co-occurs with others, suggesting synergistic mechanisms.
• Amygdalar pathobiology has implications for Alzheimer disease, Lewy body diseases, CTE, and other conditions.

Purpose of the Study:

• To review amygdalar anatomy, connectivity, vasculature, and pathology in neurodegenerative diseases.
• To investigate the role of the amygdala in the transition from benign to aggressive disease states.
• To explore the amygdala as a potential incubator for misfolded proteins.

Main Methods:

• Review of literature on amygdalar pathobiology.
• Analysis of autopsy data from the University of Kentucky Alzheimer's Disease Center cohort.
• Immunohistochemical staining of amygdalae for amyloid-beta (Aβ), Tau, alpha-synuclein, and TDP-43.

Main Results:

• Amygdalae show co-existing pathologies of multiple misfolded proteins (Aβ, Tau, α-synuclein, TDP-43).
• The amygdala may be a preferential site for the transition to aggressive neurodegenerative disease.
• Converging data suggest the amygdala plays a pivotal role in disease pathogenesis.

Conclusions:

• The amygdala may serve as an "incubator" for misfolded proteins in neurodegenerative diseases.
• Understanding amygdalar pathobiology is crucial for developing diagnostics and therapies.
• Novel misfolded protein species in the amygdala may yet be discovered.