Abstract:Down syndrome (DS) is a complex genetic syndrome characterized by intellectual disability, dysmorphism and variable additional physiological traits. Current research progress has begun to decipher the neural mechanisms underlying cognitive impairment, leading to new therapeutic perspectives. Pentylenetetrazol (PTZ) has recently been found to have positive effects on learning and memory capacities of a DS mouse model and is foreseen to treat DS patients. But PTZ is also known to be a convulsant drug at higher d… Show more
“…Thus the rescue of mortality in Dp(10)1Yey;tgAPP double mutant mice is downstream or independent of seizure occurrence. This suggests that 3 copies of Cstb do not modify tgAPP seizure occurrence, consistent with a previous report that showed an increase in Cstb copy number does not alter picrotoxin-induced seizure thresholds 21 . Figure 6 The Dp(10)1Yey segmental duplication did not alter the frequency or duration of APP transgene-associated seizures.…”
Individuals who have Down syndrome (caused by trisomy of chromosome 21), have a greatly elevated risk of early-onset Alzheimer’s disease, in which amyloid-β accumulates in the brain. Amyloid-β is a product of the chromosome 21 gene APP (amyloid precursor protein) and the extra copy or ‘dose’ of APP is thought to be the cause of this early-onset Alzheimer’s disease. However, other chromosome 21 genes likely modulate disease when in three-copies in people with Down syndrome. Here we show that an extra copy of chromosome 21 genes, other than APP, influences APP/Aβ biology. We crossed Down syndrome mouse models with partial trisomies, to an APP transgenic model and found that extra copies of subgroups of chromosome 21 gene(s) modulate amyloid-β aggregation and APP transgene-associated mortality, independently of changing amyloid precursor protein abundance. Thus, genes on chromosome 21, other than APP, likely modulate Alzheimer’s disease in people who have Down syndrome.
“…Thus the rescue of mortality in Dp(10)1Yey;tgAPP double mutant mice is downstream or independent of seizure occurrence. This suggests that 3 copies of Cstb do not modify tgAPP seizure occurrence, consistent with a previous report that showed an increase in Cstb copy number does not alter picrotoxin-induced seizure thresholds 21 . Figure 6 The Dp(10)1Yey segmental duplication did not alter the frequency or duration of APP transgene-associated seizures.…”
Individuals who have Down syndrome (caused by trisomy of chromosome 21), have a greatly elevated risk of early-onset Alzheimer’s disease, in which amyloid-β accumulates in the brain. Amyloid-β is a product of the chromosome 21 gene APP (amyloid precursor protein) and the extra copy or ‘dose’ of APP is thought to be the cause of this early-onset Alzheimer’s disease. However, other chromosome 21 genes likely modulate disease when in three-copies in people with Down syndrome. Here we show that an extra copy of chromosome 21 genes, other than APP, influences APP/Aβ biology. We crossed Down syndrome mouse models with partial trisomies, to an APP transgenic model and found that extra copies of subgroups of chromosome 21 gene(s) modulate amyloid-β aggregation and APP transgene-associated mortality, independently of changing amyloid precursor protein abundance. Thus, genes on chromosome 21, other than APP, likely modulate Alzheimer’s disease in people who have Down syndrome.
“…We paralleled our analysis of cage change day seizures, through first evaluating the role of APOE genotype in modulating seizure frequency after PTZ injection (i.e., E4FAD− and E4FAD+ vs. E3FAD− and E3FAD+). As found in other studies ( Brault et al, 2011 ; Garcia-Cabrero et al, 2013 ; Bezzina et al, 2015 ; Van Erum et al, 2020 ) PTZ administration resulted in a range of seizure-like behaviors from freezing and myoclonic twitches to tonic-clonic seizures. Overall, the incidence of the combined seizure behaviors was higher with APOE4 compared to APOE3 (97.2%, 35/36 E4FAD− and E4FAD+ mice vs. 73.5%, 25/34 E3FAD− and E3FAD+ mice, Figure 2A ).…”
Section: Resultssupporting
confidence: 82%
“…After injection, mice were placed in acrylic boxes, and behavioral changes induced by PTZ were recorded for 30 min using a video camera above the testing arena and analyzed off-line by investigators blinded to APOE genotype and sex. This dose of PTZ typically induces a range of seizure-like behaviors from freezing and myoclonic twitches to tonic-clonic seizures ( Brault et al, 2011 ; Garcia-Cabrero et al, 2013 ; Bezzina et al, 2015 ; Van Erum et al, 2020 ). Tonic-clonic seizures begin with freezing behavior alternating with myoclonic twitching of the forelimbs that progress to violent jumping and running.…”
Seizures are emerging as a common symptom in Alzheimer’s disease (AD) patients, often attributed to high levels of amyloid β (Aβ). However, the extent that AD disease risk factors modulate seizure activity in aging and AD-relevant contexts is unclear. APOE4 is the greatest genetic risk factor for AD and has been linked to seizures independent of AD and Aβ. The goal of the present study was to evaluate the role of APOE genotype in modulating seizures in the absence and presence of high Aβ levels in vivo. To achieve this goal, we utilized EFAD mice, which express human APOE3 or APOE4 in the absence (EFAD−) or presence (EFAD+) of familial AD mutations that result in Aβ overproduction. When quantified during cage change day, we found that unlike APOE3, APOE4 is associated with tonic-clonic seizures. Interestingly, there were lower tonic-clonic seizures in E4FAD+ mice compared to E4FAD− mice. Restraint handing and auditory stimuli failed to recapitulate the tonic-clonic phenotype in EFAD mice that express APOE4. However, after chemical-induction with pentylenetetrazole, there was a higher incidence of tonic-clonic seizures with APOE4 compared to APOE3. Interestingly, the distribution of seizures to the tonic-clonic phenotype was higher with FAD mutations. These data support that APOE4 is associated with higher tonic-clonic seizures in vivo, and that FAD mutations impact tonic-clonic seizures in a paradigm dependent manner.
“…Thus the rescue of mortality in Dp( 10)1Yey;tgAPP double mutant mice is downstream or independent of seizure occurrence. This suggests that 3 copies of Cstb do not modify tgAPP seizure occurrence, consistent with a previous report that showed an increase in Cstb copy number does not alter picrotoxininduced seizure thresholds (21).…”
Section: The Rescue Of App Transgene-associated Mortality By Segmental Duplication Of Prmt2supporting
Individuals who have Down syndrome (caused by trisomy of chromosome 21), have a greatly elevated risk of early-onset Alzheimer’s disease, in which amyloid-β accumulates in the brain. Amyloid-β is a product of the chromosome 21 gene APP (amyloid precursor protein) and the extra copy or ‘dose’ of APP is thought to be the cause of this early-onset Alzheimer’s disease. However, other chromosome 21 genes likely modulate disease when in three-copies in people with Down syndrome. Here we show that an extra copy of chromosome 21 genes, other than APP, influences APP/Aβ biology. We crossed Down syndrome mouse models with partial trisomies, to an APP transgenic model and found that extra copies of subgroups of chromosome 21 gene(s) modulate amyloid-β aggregation and APP transgene-associated mortality, independently of changing amyloid precursor protein abundance. Thus, genes on chromosome 21, other than APP, likely modulate Alzheimer’s disease in people who have Down syndrome.
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