DETERMINANTS OF NEURONAL VULNERABILITY IN NEURODEGENERATIVE DISEASES

Selective neuronal vulnerability can be defined anatomically by the di fferential vulnerability of circuits and neurochemically by the vulner ability of neurons that differentially express particular proteins. Th e anatomic perspective is exemplified by the vulnerability of the nigr ostriatal projection in Parkinson's disease (PD), the degeneration of upper and lower motor neurons in amyotrophic lateral sclerosis (ALS), and the preferential loss of long corticocortical projections in Alzhe imer's disease (AD). The neurochemical perspective is reflected in the heightened vulnerability of neurons that normally express high somato dendritic levels of neurofilament leg, entorhinal and association cort ices in AD, the spinal cord in a mouse model of ALS, and the retina in a primate model of glaucoma), as well as the reduced vulnerability of neurons that express calcium-binding proteins (eg, neocortex of AD pa tients, the spinal cord and brainstem of ALS patients, and the spinal cord of a mouse model of ALS). By combining neurochemical and anatomic correlates of vulnerability, an integrated view of vulnerable neurons is emerging in which characteristics of vulnerable neurons appear to transcend both brain region and disease state, suggesting that neurode generative disorders share common mechanisms of degeneration.