Summary: Changes in proteins associated with aging directly impact amyloid beta formations, a protein associated with Alzheimer’s disease.
Source: Frontiers.
Ground-breaking study opens up new area of preventative research for diseases like Alzheimer’s: Targeting age-dependent protein aggregates as possible therapeutic targets.
In a recent Frontiers in Aging Neuroscience paper, Drs. Della David and Frank Baumann together with their teams at the German Center for Neurodegenerative Diseases and Hertie Institute, showed that changes in proteins associated with aging were directly implicated in the protein formations commonly associated with Alzheimer’s disease.
Neurodegenerative diseases are often associated with protein aggregates. These are clumps of proteins created when misfolded proteins – proteins that have lost the elaborate but recognizable shape that dictates their function – assemble together to form a highly intractable structure. Recent research has also shown that even in the absence of disease, proteins can aggregate increasingly with age.
In the case of Alzheimer’s the researchers investigated whether the Amyloid beta (Aβ) aggregates closely associated with the disease could be induced by aging seeds: proteins that clump together with age to form aggregates. This would occur through a hypothesized phenomenon called cross-seeding, where different protein aggregates can induce each other’s aggregation. Crucially, the few existing examples of cross-seeding occur between disease-associated proteins.
The study’s experiments on C. elegans, an organism whose limited number of cells and relative complexity makes it an ideal test subject, showed that age-dependent protein aggregates can induce Aβ aggregation in vitro, and that the age-dependent protein aggregates of older C. elegans specimens were particularly likely to cross-seed Aβ aggregates.
In order to verify the applicability of these results to mammals, the same tests were performed in vitro on mouse brain extracts of varying age, with similar outcomes.
By performing a protein count via mass spectrometry for C. elegans, the study also identified some proteins for further investigation. The most promising candidates for cross-seeding activity were proteins present as minor components in disease-associated aggregates, which aggregate increasingly after middle-age.
Furthermore, the researchers demonstrated that one of these aggregation-prone proteins, PAR-5, can induce Aβ toxicity in vivo. According to paralysis rates, the combination of overexpressed PAR-5 with overexpressed Aβ accelerated Aβ toxicity in C. elegans.
Combined with the mass spectrometry, these experiments further highlight that certain minor components may qualify as proteins that “could be more prone to aggregate in specific brain regions and thus help the generation and spreading of disease-associated seeds in certain brain circuits.”
This study thus predicts that changes in protein conformations associated with old age may initiate Alzheimer’s disease through Aβ aggregation and toxicity.
Given that the study’s in vitro assays cannot mimic the entire complexity of the brain and picture all neurobiological interactions, the researchers encourage an “in vivo assessment by injecting age-dependent aggregates into a pre-symptomatic transgenic mouse models for Alzheimer’s disease.”
They add that aggregating proteins should be mapped in both healthy and neurodegenerative human brain samples, as a way of clarifying “which aging seeds need to be looked at and whether certain aging seeds would be more prone to seed or associate with specific disease types in specific anatomical areas.”
Funding: This work was supported by Deutsches Zentrum für Neurodegenerative Erkrankungen, Deutsche Forschungsgemeinschaft.
Source: Melissa Cochrane – Frontiers
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Full open access research for “Age-Dependent Protein Aggregation Initiates Amyloid-β Aggregation” by Nicole Groh, Anika Bühler, Chaolie Huang, Ka Wan Li, Pim van Nierop, August B. Smit, Marcus Fändrich, Frank Baumann and Della C. David in Frontiers in Aging Neuroscience. Published online May 17 2017 doi:10.3389/fnagi.2017.00138
[cbtabs][cbtab title=”MLA”]Frontiers “Study Sheds Light on Link Between Alzheimer’s and Normal Brain Aging.” NeuroscienceNews. NeuroscienceNews, 17 May 2017.
<https://neurosciencenews.com/brain-aging-neurodegeneration-6705/>.[/cbtab][cbtab title=”APA”]Frontiers (2017, May 17). Study Sheds Light on Link Between Alzheimer’s and Normal Brain Aging. NeuroscienceNew. Retrieved May 17, 2017 from https://neurosciencenews.com/brain-aging-neurodegeneration-6705/[/cbtab][cbtab title=”Chicago”]Frontiers “Study Sheds Light on Link Between Alzheimer’s and Normal Brain Aging.” https://neurosciencenews.com/brain-aging-neurodegeneration-6705/ (accessed May 17, 2017).[/cbtab][/cbtabs]
Abstract
Age-Dependent Protein Aggregation Initiates Amyloid-β Aggregation
Aging is the most important risk factor for neurodegenerative diseases associated with pathological protein aggregation such as Alzheimer’s disease. Although aging is an important player, it remains unknown which molecular changes are relevant for disease initiation. Recently, it has become apparent that widespread protein aggregation is a common feature of aging. Indeed, several studies demonstrate that 100s of proteins become highly insoluble with age, in the absence of obvious disease processes. Yet it remains unclear how these misfolded proteins aggregating with age affect neurodegenerative diseases. Importantly, several of these aggregation-prone proteins are found as minor components in disease-associated hallmark aggregates such as amyloid-β plaques or neurofibrillary tangles. This co-localization raises the possibility that age-dependent protein aggregation directly contributes to pathological aggregation. Here, we show for the first time that highly insoluble proteins from aged Caenorhabditis elegans or aged mouse brains, but not from young individuals, can initiate amyloid-β aggregation in vitro. We tested the seeding potential at four different ages across the adult lifespan of C. elegans. Significantly, protein aggregates formed during the early stages of aging did not act as seeds for amyloid-β aggregation. Instead, we found that changes in protein aggregation occurring during middle-age initiated amyloid-β aggregation. Mass spectrometry analysis revealed several late-aggregating proteins that were previously identified as minor components of amyloid-β plaques and neurofibrillary tangles such as 14-3-3, Ubiquitin-like modifier-activating enzyme 1 and Lamin A/C, highlighting these as strong candidates for cross-seeding. Overall, we demonstrate that widespread protein misfolding and aggregation with age could be critical for the initiation of pathogenesis, and thus should be targeted by therapeutic strategies to alleviate neurodegenerative diseases.
“Age-Dependent Protein Aggregation Initiates Amyloid-β Aggregation” by Nicole Groh, Anika Bühler, Chaolie Huang, Ka Wan Li, Pim van Nierop, August B. Smit, Marcus Fändrich, Frank Baumann and Della C. David in Frontiers in Aging Neuroscience. Published online May 17 2017 doi:10.3389/fnagi.2017.00138
