Summary: Age-related changes in certain proteins can directly trigger amyloid-β aggregation, a hallmark of Alzheimer’s disease.
Age-Related Protein Aggregation May Trigger Amyloid-β Formation, New Study Suggests
Researchers at the German Center for Neurodegenerative Diseases and the Hertie Institute report evidence that proteins that aggregate with age can initiate amyloid-β (Aβ) aggregation, a central feature of Alzheimer’s disease. The study, led by Drs. Della C. David and Frank Baumann and published in Frontiers in Aging Neuroscience, identifies age-dependent protein changes that could act as seeds for pathological Aβ assembly and proposes new directions for prevention and therapy.
Protein aggregation is a common feature of many neurodegenerative disorders. When proteins misfold they can clump and form insoluble aggregates that disrupt cellular function. While such aggregates are characteristic of disease, recent work has shown that protein aggregation is also a normal part of aging: hundreds of proteins become increasingly insoluble over the adult lifespan even in the absence of overt disease. The new study examines whether these age-related aggregates can directly promote disease-associated aggregation through a process called cross-seeding, in which one type of aggregate accelerates the misfolding and assembly of another.
Using the nematode Caenorhabditis elegans as a model, the research team tested whether highly insoluble proteins isolated from animals at different adult ages could seed Aβ aggregation in vitro. They found that extracts from older animals—but not from young adults—initiated Aβ aggregation. Importantly, the seeding activity was age dependent: aggregates that formed in early aging did not seed Aβ efficiently, while aggregates that accumulated from middle age onward had significantly greater seeding potential. To evaluate cross-species relevance, the authors repeated the in vitro seeding assays using brain extracts from mice of different ages and observed similar age-dependent effects.
To identify specific proteins involved in this process, the researchers performed mass spectrometry on aggregated proteins from C. elegans. Several proteins that increase their insolubility with age were identified as promising candidates because they have previously been detected as minor components within disease-associated amyloid plaques and neurofibrillary tangles. Notable examples include members of the 14-3-3 family, ubiquitin-related enzymes, and nuclear structural proteins such as Lamin A/C. These minor components may be especially prone to aggregate in certain brain regions and, by co-aggregating with disease proteins, could facilitate the formation and spread of pathological seeds in vulnerable circuits.
To test functional relevance in a living organism, the team examined PAR-5, one of the aggregation-prone proteins highlighted by proteomic analysis. In C. elegans models that overexpress human Aβ, co-overexpression of PAR-5 increased Aβ-associated toxicity, accelerating paralysis rates compared with animals expressing Aβ alone. This result supports the idea that specific age-accumulating proteins can exacerbate Aβ toxicity in vivo and may therefore play a causal role in disease initiation or progression.
While the in vitro assays and nematode experiments provide strong evidence that age-dependent aggregates can seed Aβ, the authors caution that these approaches cannot capture the full complexity of the mammalian brain. They recommend follow-up in vivo experiments, such as injecting age-dependent aggregates into pre-symptomatic transgenic mouse models of Alzheimer’s disease, to directly assess whether these aggregates initiate pathology in an intact brain environment.
The researchers also advocate mapping aggregation-prone proteins in both healthy and diseased human brain tissue. Such mapping would clarify which aging-derived seeds are most relevant to human disease and whether particular aging seeds preferentially associate with distinct neurodegenerative pathologies or anatomical regions. Identifying the most pathogenic aging seeds could guide the development of targeted interventions designed to reduce or neutralize those aggregates before disease manifests.
Implications
The study supports a model in which normal, age-associated protein misfolding is not merely a by-product of aging but may actively contribute to the initiation of neurodegenerative disease. If specific aging-related aggregates can be shown to seed pathological proteins in mammalian brains, therapeutic strategies that prevent or clear these age-dependent aggregates could represent a novel preventive approach for Alzheimer’s and other protein-aggregation disorders.
Funding: Deutsches Zentrum für Neurodegenerative Erkrankungen; Deutsche Forschungsgemeinschaft.
Source: Melissa Cochrane. Frontiers. Original research: “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, Frontiers in Aging Neuroscience, published online May 17, 2017. DOI: 10.3389/fnagi.2017.00138.
Abstract (Rewritten Summary)
Aging is the primary risk factor for neurodegenerative diseases characterized by pathological protein aggregation, including Alzheimer’s disease. Although age-related molecular changes are implicated, which specific alterations initiate disease remains unclear. Recent work has shown widespread protein aggregation during normal aging, with hundreds of proteins becoming highly insoluble over the adult lifespan. Many of these aggregation-prone proteins are also found as minor constituents in disease hallmark aggregates such as amyloid-β plaques and neurofibrillary tangles, suggesting potential cross-talk. This study demonstrates that highly insoluble proteins from aged Caenorhabditis elegans and aged mouse brains, but not from young individuals, can initiate Aβ aggregation in vitro. Seeding potential emerged during middle age rather than early adult life. Mass spectrometry highlighted late-aggregating proteins that overlap with minor components previously identified in human disease aggregates, marking them as strong candidates for cross-seeding activity. Functional tests show that one such protein, PAR-5, enhances Aβ toxicity in vivo in nematode models. These findings suggest that widespread protein misfolding with age could be critical for disease initiation and therefore represent potential targets for early therapeutic intervention.