|Budget Amount *help
¥3,300,000 (Direct Cost : ¥3,300,000)
Fiscal Year 1998 : ¥1,500,000 (Direct Cost : ¥1,500,000)
Fiscal Year 1997 : ¥1,800,000 (Direct Cost : ¥1,800,000)
We found a novel component of Alzheimer's disease (AD) amyloid, named NAC (non-Abeta component of AD amyloid) and cloned cDNA encoding NAC precursor protein, NACP.It should be noted in particular that expression pattern for NACP mirrors the distribution of typical AD pathology. The number of plaques does not necessarily correspond to the severity of cognitive impairment, while there is a strong correlation between the extent of synapse loss and the impairment. NACP is a presynaptic protein, and, therefore, some alterations of NACP including mutations could influence synaptic functions, leading to symptoms like dementia. We showed that NACP is aberrantly expressed not only in synaptic region, but also in dystrophic neurites in AD brain.
Recently, two kinds of missense mutations in the NACP gene segregating the illness were found in five independent familial Parkinson's disease (PD) pedigrees. We showed that the filamentous components of Lewy bodies, aneuropathological hallmark of PD and
of dementia with Lewy bodies (DLB) include entire molecule of NACP by immunoelectron microscopy. It was reported that recombinant NACP forms fibrils in vitro like Lewy bodies and the fibril formation is accelerated with those mutations. Thus, it is likely that the accumulation of abnormal filaments of NACP within neurons, axons, and presynaptic regions could interfere the function of neuron, i.e., neurotransmission, leading to Parkinsonisms and dementia as symptoms, and to neuronal cell death eventually. In fact, we showed that the degenerative teiminal axons of the perforant pathway in the hippocampus with DLB contain NACP-positive abnormal structures, while the origin cells of those axons contain only a few Lewy bodies, suggesting a 'dying back' degenerating process due to a blockage of axonal transport. We also revealed that not only argyrophilic glial inclusions in PD/DLB are NACP-positive, but also cytoplasmic inclusions of multiple system atrophy contain the whole NACP molecule. These findings suggest that the alteration of NACP may be involved primarily in the pathogenesis of several different neurodegenerative diseases. Less