Down syndrome (DS) is a congenital disorder caused by partial or complete
triplication of human chromosome 21. By age 40, nearly all individuals with DS develop
amyloid beta (Aβ) plaques and tau neurofibrillary tangles, the pathological hallmarks of
Alzheimer’s disease (AD). This increased susceptibility to Alzheimer’s Disease in Down
syndrome (AD-DS) has primarily been attributed to an over-dosage of the amyloid
precursor protein (APP), which generates neurotoxic Aβ fragments when cleaved by β-
secretase. However, the complete molecular mechanisms of AD-DS are not completely
understood, as trisomy of chromosome 21 can induce AD-like neuropathology
independently of APP triplication. In addition to classical AD neuropathology, enlarged,
APP-positive early endosomes appear early in AD-DS pathogenesis and are the first site
of Aβ accumulation. In AD, these endocytic abnormalities have been linked to
dysfunction of the endosomal-sorting system known as the retromer complex.
Mechanistically, retromer dysfunction can influence amyloid beta production by
increasing interaction of the retromer cargo APP with beta-secretase. However, recent
studies have also implicated the retromer complex in the development of tau pathology,
both through regulation of tau phosphorylation and degradation via lysosomes. Given that
retromer dysfunction is associated with the endosomal phenotype found in AD-DS, and
that the retromer system can modulate key aspects of AD-DS neuropathology, the
objective of the current study is to investigate the role of the retromer complex in the
development of AD-DS. We first examined the retromer system in cortices and hippocampi from human
patients with DS. Retromer recognition core proteins were significantly decreased in both the hippocampi and cortices of young and aged DS subjects compared to controls. Correlative analyses showed a significant inverse relationship between recognition core proteins and levels of soluble forms of Ab 1-40 and 1-42 in both hippocampus and cortex tissue, and phosphorylated tau epitopes PHF1 and PHF13 in the cortex of the same patients. While this does not indicate causation, these correlative analyses support the
hypothesis that dysregulation of the retromer system and AD-like pathology are closely
related. Next, we analyzed the retromer system in euploid and trisomic induced
pluripotent stem cell (iPSC) -derived neurons and observed an age-related decrease in
retromer proteins and elevation of Ab 1-40, Ab 1-42 and phosphorylated tau proteins in
trisomic neurons compared to euploid controls. Additionally, we found that
pharmacological stabilization of the retromer complex can reduce Ab and phospho-tau in
trisomic iPSC-derived neurons. While total levels of retromer proteins are unaffected, we
hypothesize that retromer function improves with TPT-172 treatment, as levels of early
endosome proteins decrease while autophagy and lysosomal proteins increase with
treatment. Treatment of trisomic neurons with TPT-172 also led to reductions in the
neuronal tau kinase CDK5 and its activator p25, providing a potential mechanistic link
between tau phosphorylation and pharmacological stabilization of the retromer system.
Additionally, we examined the effects of genetic overexpression of VPS35, the backbone
of the retromer core, in trisomic neurons. We observed similar decreases in AD pathology
measures, however, the magnitude of the effect was smaller with genetic overexpression
than with pharmacological stabilization using TPT-172. We hypothesized that trisomy 21
may can some inherent instability of the retromer system, possibly due to overabundance of retromer cargo protein APP, that is better overcome by enhancing stability of the complex rather than increasing VPS35 protein level via genetic overexpression. To further explore the role of the retromer system in the AD-DS phenotype, we performed a full characterization of cognitive function and the retromer complex at 2, 5, 9 and 12 months of age in the Ts65dn mouse model of DS. While we observed accelerated
aging related cognitive and pathological changes in DS mice, we did not observe any
protein levels changes in the retromer complex. However, because these mice do develop
endosomal dysfunction that could be indicative of retromer dysfunction, we treated mice
with TPT-172 from 4 to 9 months of age and examined cognitive function, the retromer
system and AD pathology measures. We observed improvements in cognitive function
tests and synaptic function in Ts65dn mice receiving TPT-172, as well as reductions in tau
pathology, early endosome proteins, and early endosome size. Taken together, these data demonstrate that retromer complex deficiency occurs in human DS and may contribute to the development of AD-like pathology and cognitive decline in AD-DS. Because pharmacological stabilization of the retromer system improves AD-like pathology and cognitive function in models of DS, we conclude the retromer
represents a potential therapeutic target for AD-DS. / Biomedical Sciences
| Identifer | oai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/7664 |
| Date | January 2022 |
| Creators | Curtis, Mary |
| Contributors | Pratic�, Domenico, Kim, Seonhee, Kirby, Lynn, Kishore, Raj |
| Publisher | Temple University. Libraries |
| Source Sets | Temple University |
| Language | English |
| Detected Language | English |
| Type | Thesis/Dissertation, Text |
| Format | 174 pages |
| Rights | IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available., http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | http://dx.doi.org/10.34944/dspace/7636, Theses and Dissertations |
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