Mechanisms of Neuronal Degeneration in Alzheimer's Disease

with heterotrimeric G proteins (Nishimoto et al., 1993), Alzheimer’s disease (AD) is the most common cause of and APPs can activate high conductance potassium progressive cognitive decline in the aged population. channels (Furukawa et al., 1996) and increase the activThe triad of amyloid plaques, neurofibrillary tangles, and ity of MAP kinase (Greenberg et al., 1994). However, the dementia that characterize AD was first described by relevance of these effects to the biological functions of Alois Alzheimer in 1907. Despite considerable progress APP has not been established. in elucidating the molecular components of the brain The biological functions of APP in vivo have recently lesions, the mechanism of neuronal degeneration in AD been examined in homozygous APP-knockout mice. has been unclear. However, recent advances in molecuAPP-knockout mice proceed through gestation norlar genetics have focused attention on several pathomally, suggesting that APP is not absolutely required genic mechanisms. There are now four different genes during development (Zheng et al., 1995). As adults, they that confer susceptibility to AD—the amyloid precursor exhibit a 15%–20% decrease in weight, decreased locoprotein (APP), apolipoprotein E (ApoE), and two novel motor activity, and forelimb motor abnormalities. The seven transmembrane domain proteins. Although it is only detectable abnormality in the brain is diffuse reaclikely that multiple molecular pathways can lead to AD, tive gliosis without clear evidence of neuronal degeneraa central issue is whether all causes of the disease lead tion. The minimal cortical pathology in the complete to a final common mechanism of neuronal death. This absence of APP is somewhat surprising in light of the review describes recent advances in the molecular geknown effects of APPs on neurons in vitro, raising the netics and cell biology of AD and discusses the potential possibility that the APP deficit may have been partially pathogenic mechanisms that emerge. compensated. Another mouse model has been devel-