NEUROPATHOLOGY OF THE AGING SYMPATHETIC NERVOUS SYSTEM

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DESCRIPTION: (Adapted from Applicant's Abstract) The applicants have shown that distinctive markedly enlarged terminal axons and synapses accumulate in the sympathetic nervous systems of aged experimental animals and autopsied humans, and have the pathologic features of neuraxonal dystrophy (NAD). These NAD resemble those that occur in diabetics, have a predilection for superior mesenteric and celiac ganglia, and appear to be selective for some subpopulations of nerve terminals, while completely sparing others. They now wish to test the following hypotheses: 1) that NGF participates in pathogenesis of age-related NAD; and 2) that age-dependent NAD result from abnormal synaptic plasticity, either superimposed on normal synaptic turnover or as a result of injury-induced axonal regeneration and sprouting. Their specific aims are: 1. To use the aged mouse model and several mutant mouse strains (Wallerian degeneration-delayed (Ola) and senescence accelerated) to determine whether NAD reflect an abnormality of end-organ NGF, are sensitive to exogenous pharmacologic doses of NGF, result in eventual loss of synapses, involve neurons of defined neuropeptide content or targeted endorgans, and interfere with synaptic function. 2. To test whether NAD can be precipitated in vivo by forced regeneration and sprouting of sympathetic neurons or their presynaptic terminals, and whether they develop in a culture system independent of the aged in vivo milieu. 3. To determine whether NAD in aging and diabetic human dorsal root ganglia represents pathologic sprouting of perivascular sympathetic axons and/or dorsal root ganglion neurons.