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.
Highlights
Down syndrome (DS), associated with trisomy 21 (Ts21), occurs in 1 in ∼800 live births, leading to an estimated 200,000–250,000 people with this condition in the US (Bull, 2020)
In addition to disrupting early endosomes, C-terminal APP fragment of amino acids (β-CTF) was shown to mediate Amyloid Precursor Protein (APP)-induced dysfunction of the lysosomal system through affecting the expression and maturation and/or activity of lysosomal enzymes including cathepsin D, possibly through APP-induced abnormal lysosomal acidification in DS fibroblasts and the Ts2 mouse model (Jiang et al, 2019). These findings were supported in studies in an Alzheimer’s disease (AD) mouse model (3xTgAD) and adeno-associated viral-mediated β-CTFinfected mice (Lauritzen et al, 2016; Figure 2A)
This study showed that reductions in PARKIN and PINK1 impaired initiation of mitophagy, together with hyperactivation of mammalian target of rapamycin (mTOR) (Bordi et al, 2019)
Summary
Down syndrome (DS), associated with trisomy 21 (Ts21), occurs in 1 in ∼800 live births, leading to an estimated 200,000–250,000 people with this condition in the US (Bull, 2020). The roles of App gene dose in abnormal endosome phenotypes and deficient axonal transport of neurotrophin signaling were further supported by a recent study in which Posiphen reversed Rab hyperactivation, restored the size of early endosomes, and restored retrograde axonal transport of neurotrophins in primary cortical Ts65Dn neurons and of neurotrophin signaling in the Ts65Dn brains, with the drug acting, at least in part, through reducing the levels of APP and CTFs in a translationdependent manner In addition to disrupting early endosomes, β-CTF was shown to mediate APP-induced dysfunction of the lysosomal system through affecting the expression and maturation and/or activity of lysosomal enzymes including cathepsin D, possibly through APP-induced abnormal lysosomal acidification in DS fibroblasts and the Ts2 mouse model (Jiang et al, 2019) These findings were supported in studies in an AD mouse model (3xTgAD) and adeno-associated viral-mediated β-CTFinfected mice (Lauritzen et al, 2016; Figure 2A). Both genetic ablation and pharmaceutical inhibition of USP25 reduced microglia-mediated neuroinflammation and restored synaptic and cognitive function in the 5xFAD mouse model of AD (Zheng et al, 2021)
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