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Neurodegeneration in Aging
Neurodegeneration in Aging
Neurodegeneration refers to the progressive loss of structure and function of neurons, which is the primary pathological feature of age-related neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease.
Unfortunately the molecular cues that initiate the degeneration of neurons during aging are still largely unknown.
There is an emerging concept that the degeneration of neurons can be regulated non-cell-autonomously by surrounding cells, such as astrocytes and microglia. From a broader perspective, a significant amount of evidence indicates that some age-related neurodegenerative diseases, such as Alzheimer’s disease, are not only a central nervous system disorder but also have systemic pathology and manifestations, suggesting a close link between the non-neuronal periphery and neurons during the process of aging. This could be the key for us to identify how exactly neurodegeneration is switched on by aging, and therefore may lead to the development of new therapeutic approaches for neurodegenerative diseases.
C. elegans
C. elegans
Caenorhabditis elegans (C. elegans) is a small free-living transparent roundworm. For adult worms, they are about 1mm in length. Because of its relatively short lifespan along with its powerful genetic tractability, C. elegans has been widely used in aging research over the past few decades. They are also optically transparent throughout their lifespan, allowing easy in-vivo observation of the morphology/structure of neurons, which makes it a perfect model system to study aging-associated neurodegeneration and the underlying molecular mechanisms.
Using C. elegans to study aging-associated neurodegeneration
With a variety of approaches in genetics, molecular biology, and cell biology as well as in vivo live imaging techniques
FLP neuron:: GFP
FLP neuron:: GFP
Top: Younger adult
Bottom: Older adult
PLM neuron:: GFP
PLM neuron:: GFP
Top: Younger adult
Bottom: Older adult
PVD neuron:: GFP
PVD neuron:: GFP
Top: Younger adult
Bottom: Older adult
Aging of non-neural tissues & neuronal aging
Aging of non-neural tissues & neuronal aging
Different organs, tissues and cells age at different rates. The interaction between non-neuronal cells/tissues and neurons over the course of aging may play a key role in providing the upstream cues for the initiation of neurodegeneration. We are currently investigating how this might work, from two perspectives: the aging signaling in non-neuronal tissues and morphological/structural aging of non-neuronal tissues.
Antimicrobial peptides & neurodegeneration
Antimicrobial peptides & neurodegeneration
Antimicrobial peptides (AMPs) are a group of small peptides produced as the first line of defense in all classes of life, from worms, flies, to rodents and human, to function as endogenous antibiotics in response to microbial infections. Our previous research using C. elegans has discovered an unexpected function of a skin-expressed antimicrobial peptide in causatively triggering aging-associated degeneration of sensory neurons, by binding and activating their specific neuronal receptors (E et al, Neuron, 2018). We are currently investigating whether other AMPs from non-neuronal tissues also have neurodegeneration-inducing effects. The studies may help answer an intriguing question: Do AMPs serve as a universal etiological factor in neuronal aging?
Inter-individual variation in neuronal aging
Inter-individual variation in neuronal aging
Aging is natural to all of us, but the nervous systems in different individuals exhibit different susceptibilities to the negative consequences of aging. Wild-type C. elegans (self-fertilizing hermaphrodites) have high genetic homogeneity under standard lab conditions. Yet, there is a big inter-individual variation in the time-course of aging-associated neurodegeneration. We are exploring what molecular mechanisms underlie this phenotypic plasticity in neuronal aging, with a focus on the genes and pathways that are highly conserved between worms and mammals.
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