NIH VideoCast - NIH ProtIG Seminar: The role of long-lived proteins in aging and Alzheimer’s disease

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NIH ProtIG Seminar: The role of long-lived proteins in aging and Alzheimer’s disease

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Air date:	Thursday, December 14, 2023, 1:00:00 PM Time displayed is Eastern Time, Washington DC Local
Views:	Total views: 143 (13 Live, 130 On-demand)
Category:	Special
Runtime:	01:02:06
Closed captioning:	Check box to display CC outside of the video Note: You can drag the captioning window around and resize it
Description:	Loss of proteostasis is a hallmark of aging, and aging is the greatest risk factor for Alzheimer's disease (AD). Deterioration in function and accumulation of damage to the proteome are largely repaired by protein turnover. These turnover mechanisms are particularly important in long-lived postmitotic neurons, which cannot dilute toxic proteins through cell division. We aimed to identify extremely long-lived proteins (ELLP) that persist for several months or longer across the aging continuum in wild-type mice and in genetic AD mouse models. We hypothesize that these ELLPs represent key points of vulnerability to the decline of the aging proteome and critical substrates of amyloid pathology.To identify ELLPs relevant to AD, we used whole-animal metabolic stable isotope labeling of wild-type and amyloid precursor protein knock in (App KI) mice combined with bottom-up proteomic analysis using liquid chromatograph-tandem mass spectrometry. The results were verified and followed up using biochemical, molecular, and electrophysiological methods. In wild-type mice we discovered that the brain proteome uniquely undergoes dynamic global turnover fluctuations during aging compared to heart and liver tissue. Parallel analyses of the insoluble fraction revealed that several protein sub-complexes experience impaired turnover, in part due to misfolding. Finally, we discovered that age-associated fluctuations in the activity of the ubiquitin proteasome system are linked to the turnover of the catalytic core subunits.In App KI mice, the turnover of presynaptic proteins is selectively impaired in the early stages of Abeta accumulation. Synaptic vesicle (SV)-associated proteins, have elevated levels, misfold in plaque-independent manner, and interact with APP and Abeta. We also found an enlargement of the SV pool and an increase in presynaptic potentiation. The identification of ELLPs provides a rare opportunity to uncover Achillies heals of aging and initial substrates of amyloid pathology.

Author:	Jeffery N. Savas, Northwestern University

CIT Live ID:	53958
Permanent link:	https://videocast.nih.gov/watch=53958

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