Subtle changes in the aging human brain, such as neuronal sprouting and restructuring, are thought to underlie cognitive decline and may promote neuronal dysfunction in Alzheimer's and other late-onset neurodegenerative disease. Currently we understand too little of these processes and their consequences to harness knowledge for design of therapeutic intervention. We study fundamental processes relevant to neuronal aging in C. elegans. In this transparent 959-celled animal, we can directly observe individual fluorescently labeled neurons, as well as fluorescently tagged protein aggregates and mitochondria. Recently, we carefully documented how some C. elegans neurons physically change as animals grow old. We find that like human brain aging, there is little neuron loss as C. elegans ages. However, some types of neurons exhibit dramatic novel branching and outgrowth with age;such neurons might have diminished function. We can score this dramatic age-associated dendritic restructuring using a high-magnification dissecting microscope, which facilitates relatively rapid analysis of individual neurons within live, aging animals. Defining th mechanisms by which adult nervous systems maintain their structural integrity and elaborating on the poorly understood mechanisms of age-associated dendritic restructuring is of considerable importance to both normal aging and neurodegenerative disease. We will combine use of fluorescent reporters with genetic manipulations to address three aims:
Aim 1 is to define the relationship of proteostasis disruption and dendritic restructuring in individual aging neurons Aim 2 is to define the relationship between mitochondrial status and age-associated dendritic restructuring in individual aging neurons. This study will also break new ground in characterizing the basic cell biology of the aging mitochondrial populations in individual neurons in native context.
Aim 3 is to screen candidate gene sets to identify novel factors that influence the maintenance of structural integrity of the aging nervous system. Our studies should address gaps in understanding of the basic biology by which structural maintenance is accomplished in a mature nervous system and inform on mechanisms and interventions that may better maintain the integrity and function of the aging human nervous system.
Even healthy aging of the human brain is associated with synaptic changes and aberrant sprouting in neurons, which have been proposed to underlie cognitive decline. Such changes appear exacerbated in Alzheimer's disease, a late onset disease for which age itself is the major risk factor. Exactly how aging becomes permissive for neuronal deterioration and disease susceptibility remains a mystery. Recently, we discovered that some neurons in aging C. elegans exhibit aberrant branching and outgrowth, and we have documented a global decline of synaptic structures with age, suggesting that fundamental neuronal aging mechanisms may be conserved from simple animals to humans. We plan to identify genetic factors that influence the structural maintenance of the adult nervous system by exploiting the experimental advantages of a powerful genetic model. Our planned work will address gaps in our understanding that might ultimately suggest novel and efficacious therapies to combat human brain aging.
|Laker, Rhianna C; Xu, Peng; Ryall, Karen A et al. (2014) A novel MitoTimer reporter gene for mitochondrial content, structure, stress, and damage in vivo. J Biol Chem 289:12005-15|