Alzheimer disease (AD) is characterized by progressive cognitive decline caused by synaptic dysfunction and neurodegeneration in the brain, and late-onset AD (LOAD), genetically classified as a polygenetic disease, is the major form of dementia in the elderly. It has been shown that b amyloid, deposited in the AD brain, interacts with dynamin 1 and that the dynamin 2 (DNM2) gene homologous to the dynamin 1 gene is encoded at chromosome 19p13.2 where a susceptibility locus has been detected by linkage analysis. To test the genetic association of LOAD with the DNM2 gene, we performed a casecontrol study of 429 patients with LOAD and 438 sex-and age-matched control subjects in a Japanese population. We found a significant association of LOAD with single nucleotide polymorphism markers of the DNM2 gene, especially in non-carriers of the apolipoprotein E-e4 allele. Even though subjects with the genotype homozygous for the risk allele at rs892086 showed no mutation in exons of the DNM2 gene, expression of DNM2 mRNA in the hippocampus was decreased in the patients compared to non-demented controls. We propose that the DNM2 gene is a novel susceptibility gene for LOAD.
Background: Accumulation of β-amyloid is a major pathology of Alzheimer's disease (AD). As in other neurodegenerative diseases, it is also reported that proteasome activity is deteriorated in post-mortem brains of AD patients. However, the mechanism of proteasomal dysfunction in AD remains unexplained. There is, however, increasing reported evidence that the unfolded protein response (UPR) is involved in AD pathology. Here we show that Aβ causes not only the UPR leading to endoplasmic reticulum (ER) stress mediated cell death, but also proteasomal dysfunction in cultured cells. Methods: Mouse primary cultured neurons and other cultured cells such as HEK 293T or SH-SY5Y were treated with Aβ or other reagents, such as thapsigargin and lactacystin, to study UPR or proteasome activity. The UPR was investigated using proteins or mRNA expression. To ascertain proteasome activity, we also recruited SH-SY5Y cells stably transfected with GFP u . Results: In vitro study showed that UPR, phosphorylation of eIF-2α and BiP degradation preceded proteasome dysfunction. It is known that the UPR of ER occurs with the assistance of proteasome as ER-associated protein degradation (ERAD). Conclusion: This evidence, taken together, suggests that Aβ may induce proteasome dysfunction by preceding the UPR through ER-associated protein degradation.
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