Depletion of TDP-43 decreases fibril and plaque beta-amyloid and exacerbates neurodegeneration in an Alzheimer%26apos;s mouse model

作者：LaClair Katherine D; Donde Aneesh; Ling Jonathan P; Jeong Yun Ha; Chhabra Resham; Martin Lee J; Wong Philip C

来源：Acta Neuropathologica, 2016, 132(6): 859-873.

DOI：10.1007/s00401-016-1637-y

• TDP-43
• Alzheimer's disease
• beta-Amyloid
• Nuclear depletion
• Forebrain

TDP-43 proteinopathy, initially associated with ALS and FTD, is also found in 30-60% of Alzheimer's disease (AD) cases and correlates with worsened cognition and neurodegeneration. A major component of this proteinopathy is depletion of this RNA-binding protein from the nucleus, which compromises repression of non-conserved cryptic exons in neurodegenerative diseases. To test whether nuclear depletion of TDP-43 may contribute to the pathogenesis of AD cases with TDP-43 proteinopathy, we examined the impact of depletion of TDP-43 in populations of neurons vulnerable in AD, and on neurodegeneration in an AD-linked context. Here, we show that some populations of pyramidal neurons that are selectively vulnerable in AD are also vulnerable to TDP-43 depletion in mice, while other forebrain neurons appear spared. Moreover, TDP-43 depletion in forebrain neurons of an AD mouse model exacerbates neurodegeneration, and correlates with increased prefibrillar oligomeric A beta and decreased A beta plaque burden. These findings support a role for nuclear depletion of TDP-43 in the pathogenesis of AD and provide strong rationale for developing novel therapeutics to alleviate the depletion of TDP-43 and functional antemortem biomarkers associated with its nuclear loss.

• 出版日期2016-12