Inflammatory mechanisms and anti-inflammatory therapy in Alzheimer's disease

OVERVIEW of this volume with a short history of the subject: Alzheimer's disease (AD) is a progressive dementing illness that causes neurodegeneration in highly selective regions of the forebrain. Remarkable recent progress from genetic approaches has led to the identification of relatively infrequent familialassociated AD genes on chromosomes 1, 14, and 21. A greater portion of the familial and sporadic AD cases are associated with inheritance of the apoE4 allele on chromosome 19. Nonetheless, little is understood about how this diverse array of genes leads to such similar pathologic endpoints or what the optimum treatments might be for therapy or prevention. Similarly, intensive studies of the two prominent hallmarks of AD neuropathology; neuritic plaques and neurofibrillary tangles, have revealed much about cellular and molecular processes. However, we do not yet know the primary causes of neurodegeneration from genetic or possible environmental causes. Interventions to supplement failing neurotransmitter systems or heroic efforts to provide beneficial neurotrophic factors have so far addressed only single aspects of the multisystem, highly selective, neurodegeneration that is characteristic of this disease. The first mechanisms and therapeutic targets to be seriously studied in AD derived from the seminal observations of Bowen et al. (2) and Davies and Maloney in 1976 (6), that postmortem AD brains typically showed > 50% deficits in choline acetyl transferase. The neurochemical and neuronal deficits in the forebrain cholinergic system in AD were consistent with a crucial role of cholinergic functions in memory and the greater sensitivity of older individuals to memory impairments from acetylcholinesterase inhibitors (7). We all recognize the major field that has developed from these early observations. While the cholinergic strategy continues to be explored clinically on a large scale, antiinflammatory drugs have recently entered the therapeutic race. The editors of this volume believe that therapies designed to slow or halt the disease at all sites of involvement must target fundamental pathologic processes of the disease. By recent evidence, one such process may be the glial reactions and other manifestations of inflammatory reactions in AD brains. Gliosis was recognized by Alois Alzheimer in his first description of AD brain (1). The presence of activated astrocytes and