Factors which influence Abeta levels, rather than overexpression of APP, may account for the differences in age at onset of dementia in Down's syndrome.
The presence of this PS1 mutation has an even greater effect on both vascular and parenchymal amyloid deposition, than the overexpression of the amyloid beta precursor protein present in DS patients, suggesting that PS mutations can be a critical factor determining amyloid deposition.
To better understand how the Down syndrome context results in increased vulnerability to Alzheimer's disease, we analysed amyloid-β [25-35] peptide toxicity in the Tc1 mouse model of Down syndrome, in which ~75% of protein coding genes are functionally trisomic but, importantly, not amyloid precursor protein.
Overexpression of DSCAM in Down syndrome (DS) may be involved in the pathogenesis of mental retardation through an inhibitory action on synaptogenesis/neurite outgrowth, and in the precocious dementia associated with an amyloid precursor protein (APP) dosage effect with enhanced plaque formation.
This may be the case during pathological evolution of AD and DS when beta/A4 derived from synaptic APP is converted to beta/A4 amyloid by radical generation.
Down syndrome (DS) arises from a triplication of chromosome 21, causing overproduction of the amyloid precursor protein and predisposes individuals to early Alzheimer's disease (AD).
In addition to longevity, the amyloid precursor protein gene located on chromosome 21 places individuals with DS at a high risk for developing Alzheimer disease.
Concentrations of Aβ<sub>40</sub> and Aβ<sub>42</sub> were much higher in adults with DS than in other groups, reflecting APP gene triplication, while no difference in the Aβ<sub>42</sub>/Aβ<sub>40</sub> ratio between those with DS and sAD may indicate similar processing and deposition of Aβ<sub>40</sub> and Aβ<sub>42</sub> in these groups.
Further, the manifestation and time course of behavioral yet not neuropathological symptoms in betaAPP mutant mice resemble in some aspects those of the human Down's syndrome.
Using astrocytes and neuronal cultures from DS fetuses, a recent paper shows that altered metabolism of the amyloid precursor protein and oxidative stress result from mitochondrial dysfunction.1 These findings are consistent with considerable data implicating the role of the mitochondrial genome in DS pathogenesis and aetiology.
A four- to fivefold overexpression of the gene for the Alzheimer amyloid precursor protein (APP) in individuals with Down's syndrome (DS) appears to be responsible for the fifty year earlier onset of Alzheimer's disease pathology in DS compared to the normal population.
Three mutations (-118C-->A, -369C-->G, and -534G-->A) identified only in patients with AD showed, in vitro, a nearly twofold neuron-specific increase in APP transcriptional activity, similar to what is expected from triplication of APP in Down syndrome.
Aggregates of U1 snRNP-immunoreactivity formed cytoplasmic tangle-like structures in cortex of AD subjects with PS1 and amyloid precursor protein (APP) mutations as well as trisomy 21.
Aberrant expression of the amyloid precursor protein (APP) gene may contribute to the beta-amyloid deposition seen in Alzheimer's disease and Down syndrome patients.
In delaying the age of onset, the epsilon2 allele would have a similar action in AD-type dementia in DS and in AD families with amyloid precursor protein (APP) mutations.
We demonstrated significant overexpression of amyloid precursor protein (APP) in DS placentas at RNA and protein levels by real-time quantitative PCR, Western blot analysis, and immunohistochemistry.
We conclude that ETS2 is a transcriptional regulator of beta-APP and that overexpression of ETS2 in DS may play a role in the pathogenesis of the brain abnormalities in DS and possibly AD.
Genes that are overexpressed in DS (APP, DSCAM, MNB/DYRK1A, and RCAN1) produce proteins critical for neuron and synapse growth, development and maintenance.
Here, we demonstrate that exosome-enriched extracellular vesicles (hereafter called EVs) isolated from DS and Ts2 brains, and from the culture media of human DS fibroblasts are enriched in APP carboxyl-terminal fragments (APP-CTFs) as compared with diploid controls.