PROGRESSIVE NEURONAL INJURY ASSOCIATED WITH AMYLOID PLAQUE-FORMATION IN ALZHEIMER-DISEASE

Neuronal injury associated with amyloid plaque progression in Alzheime r disease was examined using TUNEL combined with beta-amyloid immunola beling. There was a progressive increase in the frequency of TUNEL-pos itive neurons associated with plaque types representing a hypothesized sequence of plaque evolution, from 20% of neurons nor associated with plaques to 40%, 70-80%, and 100% of neurons in diffuse, neuritic, and dense-core non-neuritic plaques, respectively. The total number of ne urons associated with end-stage, dense-core, non-neuritic plaques decl ined by 70% (per unit plaque area) compared with neuritic plaque forms . This decline, together with the fact that virtually all of those rem aining were TUNEL-positive, suggests that neuronal cell damage increas es as plaques evolve from diffuse to more complex forms and that event ually all plaque-associated neurons are lost. This novel demonstration of neurotoxicity associated with amyloid plaque formation and progres sion suggests that plaque-associated neuronal injury is a major cause of neuronal loss in Alzheimer disease.