MECHANISMS 0F RETINAL DEFECTS IN ALZHEIMERS DISEASE

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Our recent report (Hinton, Sadun, Blanks and Miller, 1986; refer to Appendix item No. 3) documented the involvement of the retina in the constellation of neurodegenerative changes present in Alzheimer's disease (AD). Preliminary analyses of retinal whole- mounts, together with the widespread axonal degeneration seen in the optic nerves of AD patients, suggest that the retinal ganglion cells of AD patients are degenerating in high numbers. The retinal changes in the ganglion cell layer are particularly intriguing, since they are not associated with neurofibrillary tangles or neuritic plaques, suggesting that these features are not requisite for the neuronal loss found in AD. This project will focus on the histopathology found in retinas of AD patients compared with retinas of age-matched "controls". Studies will include: (1) a morphometric analysis of retinal whole-mounts and radial sections to determine the number, size and distribution of the remaining ganglion cells, and (2) an evaluation of the cholinergic neurotransmitter system, in the retina. The latter aspect of the project is extremely important as abnormally low levels of acetylcholine (ACh) are suspected to play a major role in the pathogenesis of AD. The retina may also exhibit abnormalities in the cholinergic neurotransmitter system, similar to those found in the hippocampus, frontal cortex and nucleus basalis of AD patients. (3) We will determine if there is selective damage to the neuropeptides in the retina, since there are reports of a subclass of somatostatin-positive neurons and of neuropeptide Y neurons that are affected in AD. (4) Finally, we will determine if vascular pathology exists in the retinas of AD patients. We will measure basement membrane thickness in retinal capillaries at the electron microscopic level and determine the density of blood vessels using the lectin RCA (Ricinis communis A) as a vascular marker. The results of these studies on retinal tissues will be correlated with the severity of the disease and with the neurodegenerative changes in the central nervous system of the AD patients. Improved understanding of the degenerative changes that occur in AD will help define a particular class of neurons that is vulnerable to the pathologic process, and should help to elucidate the degenerative processes that underlie this devastating disease.