Transactive Response DNA-Binding Protein 43 Burden in Familial Alzheimer Disease and Down Syndrome

Abstract

Transactive response DNA-binding protein 43 (TDP-43) is a nuclear ribonucleoprotein that plays a role in a variety of cellular functions including protein processing, particularly, modulating transcription and exon splicing.¹ It is also a major pathological hallmark of ubiquitinated inclusions in amyotrophic lateral sclerosis and forms of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U,^2,3 more recently abbreviated FTLD-TDP by Mackenzie et al⁴). In these conditions, both sporadic and familial cases show abnormal accumulation of hyperphosphorylated, ubiquitinated, and truncated TDP-43 fragments.^2,3 Recently, we developed phosphorylation-specific TDP-43 monoclonal antibodies that recognize only pathological TDP-43, to study the altered phosphorylation patterns of abnormal TDP-43 in amyotrophic lateral sclerosis, FTLD-TDP, and other neurodegenerative diseases.⁵ These and other studies with previously reported anti–TDP-43 antibodies have shown that phosphorylation of S 409/410 in TDP-43 is detected in neuronal and glial inclusions of a variety of central nervous system (CNS)–degenerative diseases including Alzheimer disease (AD) as well as in other older individuals with cognitive impairment.^5-8 There is also an association between cognitive status and the intensity of TDP-43 pathology in subjects with age-related cognitive impairment.⁷ Interestingly, in the Nelson et al study,⁷ there was no association between cognitive status and other pathology, including AD neuropathological features such as amyloid plaque or neurofibrillary tangle burden. Together, these data raise the possibility that TDP-43 plays a significant role in the pathogenic mechanisms underlying cognitive impairment in AD and other age-related brain disorders.