Mechanistic Analysis of Age-Related Clinical Manifestations in Down Syndrome

Abstract

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.

Keywords: Alzheimer’s disease; COVID-19; Down syndrome; hearing loss; infection; mechanisms.

Figure 1

(A) The relationship between Hsa21 and age-related clinical phenotypes. (B) Hsa21 gene orthologs which play important roles in Down syndrome (DS)-associated dementia and other age-related clinical phenotypes.

Figure 2

Schematic representations of the specific examples of the relationship between the triplication of Hsa21 or Hsa21 gene ortholog(s) and its phenotypic consequences at various levels. (A) The triplication of the APP ortholog and its impacts on Alzheimer’s disease (AD)-related phenotypic features: increased APP gene dose in DS leads to increases in full-length APP protein and its products, including CTF (α-CTF and β-CTF) and Aβ peptides of varying length. Accumulating evidence points to β-CTF as driving endosomal dysfunction, lysosomal dysregulation, autophagy impairment as well as mitochondrial dysfunction. Abnormal early endosomes may contribute to deficits in the retrograde axonal transport of neurotrophic signaling in several neuron populations, including BFCNs, thus compromising their trophic support and leading to neuronal dysfunction and atrophy. Lysosomal dysregulation and autophagy impairment can allow for the build-up of toxic proteins and induce oxidative stress due to failed clearance of organelles, including mitochondria. β-CTF accumulation could also lead to mitochondrial dysfunction. In addition, increased Aβ peptides contribute to amyloid plaque formation; evidence supports a role for Aβ in tau pathology, but as yet there is no direct demonstration for this in DS. Autophagy-lysosomal system dysfunction also contributes to amyloid and tau pathologies. (B) The triplication of Hsa21 or Hsa21 gene orthologs and its impacts on the immune system and COVID-19 in the DS population: The dosage increase of the four interferon receptor genes in Ts21, IFNAR1, IFNAR2, IFNGR2, and IL10RB, up-regulates expression of interferon-stimulated genes (ISGs), which in turn results in immune dysregulation, including alteration of immune cell numbers as well as an imbalance between pro-inflammatory and anti-inflammatory mediators. These changes in DS are likely related to a higher risk for more severe COVID-19, which may also be contributed by the dosage increase of TMPRSS2 and early aging. BFCNs, basal forebrain cholinergicneurons; α-CTF, C-terminal APP fragment of 83 amino acids.