REGENERATIVE FAILURE - A POTENTIAL MECHANISM FOR NEURITIC DYSTROPHY IN ALZHEIMERS-DISEASE

Although neuronal pathology and synaptic loss are salient features of Alzheimer's disease (AD), the underlying mechanisms involved are unkno wn. Using double-immunolabeled preparations, we found that both the de nsity and the total lengths of axons are decreased within the A beta-c ontaining area of senile plaques (SP) in comparison with the adjacent neuropil. These observations suggest that axotomy is occurring in the vicinity of the SP which could account for the synaptic loss. Since A beta in solution has been shown to be neurotoxic in vitro, we tested w hether intact SP cores isolated from AD brain were equally detrimental when presented to retinal ganglion neurons. Surprisingly, SPs did not appear to be toxic or even repulsive to neurons since they adhered we ll and elaborated axons which wrapped tightly around the SP core. In t he presence of cortical astrocytes, however, neurons appeared to avoid SP cores. We found that astrocytes accumulate and deposit chondroitin sulfate proteoglycans (CSPGs) around SP cores in vitro in a pattern s imilar to that observed around SPs in Alzheimer's disease brain. Neuro nal avoidance of astrocyte-conditioned SP cores could be due to the ax on outgrowth inhibitory nature of CSPGs. These results suggest that as trocytic reaction to SPs, including increased CSPGs, may facilitate th e decreased axon density and synaptic loss in AD brain. Moreover, the similarities between swollen axon endings following axotomy in trauma and the dystrophic neurites of the SP suggest that dystrophic neurites in AD may be exhibiting regenerative failure rather than aberrant spr outing. (C) 1996 Academic Press, Inc.