Mechanistic Analysis of Age-Related Clinical Manifestations in Down Syndrome

Frontiers in Aging Neuroscience

Quang-Di Chen¹  Richard J. Salvi¹  Xuming Zhang²  William C. Mobley³  Xu-Qiao Chen³  Y. Eugene Yu⁴  Benjamin Tycko⁵  Zhuo Xing⁷ 

[1] Department of Communicative Disorders and Sciences and Center for Hearing and Deafness, University at Buffalo, Buffalo, NY, United States;Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR, United States;Department of Neurosciences, University of California San Diego, La Jolla, CA, United States;Genetics, Genomics and Bioinformatics Program, State University of New York at Buffalo, Buffalo, NY, United States;Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, United States;Hackensack-Meridian Health Center for Discovery and Innovation, Nutley, NJ, United States;The Children’s Guild Foundation Down Syndrome Research Program, Genetics and Genomics Program and Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States;

关键词: Down syndrome;    Alzheimer’s disease;    hearing loss;    infection;    COVID-19;    mechanisms;   

DOI  :  10.3389/fnagi.2021.700280

来源: DOAJ

【 摘 要 】

Down syndrome (DS) is the most common genetic cause of Alzheimer’s disease (AD) due to trisomy for all or part of human chromosome 21 (Hsa21). It is also associated with other phenotypes including distinctive facial features, cardiac defects, growth delay, intellectual disability, immune system abnormalities, and hearing loss. All adults with DS demonstrate AD-like brain pathology, including amyloid plaques and neurofibrillary tangles, by age 40 and dementia typically by age 60. There is compelling evidence that increased APP gene dose is necessary for AD in DS, and the mechanism for this effect has begun to emerge, implicating the C-terminal APP fragment of 99 amino acid (β-CTF). The products of other triplicated genes on Hsa21 might act to modify the impact of APP triplication by altering the overall rate of biological aging. Another important age-related DS phenotype is hearing loss, and while its mechanism is unknown, we describe its characteristics here. Moreover, immune system abnormalities in DS, involving interferon pathway genes and aging, predispose to diverse infections and might modify the severity of COVID-19. All these considerations suggest human trisomy 21 impacts several diseases in an age-dependent manner. Thus, understanding the possible aging-related mechanisms associated with these clinical manifestations of DS will facilitate therapeutic interventions in mid-to-late adulthood, while at the same time shedding light on basic mechanisms of aging.

【 授权许可】

Unknown