Abstract：
:Alzheimer's disease (AD) is the most prevalent form of dementia in the world. The neuropathological characteristics of AD patients are the accumulation of extracellular plaques of β-amyloid (Aβ) and intracellular hyperphosphorylated tau protein. Transthyretin (TTR) may alleviate AD symptom by reducing Aβ concentration in the brain. There were reports for a decreased TTR level in both AD brain and blood. However, there is still no robust evidence to support the genetic association of the TTR gene with AD. In this study, we aimed to investigate the potential association of TTR variation with AD by directly sequencing the whole exons and the promoter region of the TTR gene in 529 AD patients and 334 healthy controls from Han Chinese population. We found no association between TTR common variants and AD but observed an enrichment of TTR rare variants in AD patients relative to controls. Further in silico prediction analysis and functional assessment at the cellular level identified four potentially pathogenic rare variants in AD patients. In particular, variant c.-239C>A could potentially downregulate the TTR promoter activity; c.200+4A>G might influence the constitutive splicing of TTR mRNA; c.148G>A (p.V50M) and c.332C>T (p.A111V) would change the structure of TTR and decrease its Aβ-binding ability. Our results provided direct genetic evidence to support the active involvement of TTR in AD.
journal_name
Mol Neurobioljournal_title
Molecular neurobiologyauthors
Xiang Q,Bi R,Xu M,Zhang DF,Tan L,Zhang C,Fang Y,Yao YGdoi
10.1007/s12035-016-0065-2subject
Has Abstractpub_date
2017-09-01 00:00:00pages
5192-5200issue
7eissn
0893-7648issn
1559-1182pii
10.1007/s12035-016-0065-2journal_volume
54pub_type
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