Gene Dosage Dependent Aggravation of the Neurological Phenotype in the 5XFAD Mouse Model of Alzheimer's Disease

Abstract

In the present report, we extend previous findings in the 5XFAD mouse model with regard to a characterization of behavioral deficits and neuropathological alterations. We demonstrate that these mice develop a robust age-dependent motor phenotype and spatial reference memory deficits when bred to homozygosity, leading to a strongly reduced age of onset of behavioral symptoms. At postnatal day sixteen, abundant AβPP was detected in subiculum and cortical pyramidal neurons. From six weeks on, intraneuronal Aβ could be detected which was much more abundant in homozygous mice. The same gene-dosage effect was seen on memory and motor deficits. While at 2 months of age neither heterozygous nor homozygous 5XFAD mice show any neurological phenotype except for alterations in anxiety behavior, at 5 months they were clearly evident. Interestingly, despite abundant motor deficiencies, homozygous 5XFAD mice were able to perform the acquisition training of the Morris water maze task with no difference in the swimming performance between the groups. Therefore the aggravated spatial memory and spatial reference memory deficits of the homozygous mice correlated with the elevated soluble and insoluble Aβ levels. Homozygous 5XFAD mice represent a model with several advantages in comparison to the heterozygous mice, developing amyloid pathology much more rapidly together with a neurological phenotype. These advantages allow reducing the number of animals for Alzheimer's disease research.

N-truncated Aβ4–x peptides in sporadic Alzheimer’s disease cases and transgenic Alzheimer mouse models

“…APP/PS1KI mice were a generous gift of Dr. Laurent Pradier, Sanofi-Aventis, Paris, France. The analysis of 5XFAD mice (Tg6799) has also been reported previously [ 27 , 28 ]. 5XFAD mice overexpress APP695 carrying the Swedish, Florida, and London mutations under the control of the murine Thy-1 promoter.…”

“…The Aβ 4–x plaque load was quantified using 9-month-old hemi- and homozygous 5XFAD mice ( n = 3–4) [ 28 ]. In brief, three paraffin sections per animal were stained simultaneously with DAB.…”

Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice

“…We found a statistically significant CAW treatment-dependent increase in these synaptic markers in the cortex, while there was a significant increase in synaptophysin in the hippocampus and an increasing trend in Psd95 (p=0.026) with CAW treatment. An interesting observation in the progression of 5XFAD pathology is that spine loss (4-9 months) [62] occurs subsequent to cognitive dysfunction (3-6 months) [35,[63][64][65][66] and Aβ plaque formation (two months) [67]. This is different from the progression in Tg2576, which manifests synaptic damage at an early stage of pathological development (4.5 months) [68,69] with a corresponding decrease in synaptic density markers [70] prior to Aβ plaque development (10 months) [71] and cognitive deficiencies (one year) [72,73].…”

Exposure of Mesenchymal Stem Cells to an Alzheimer’s Disease Environment Enhances Therapeutic Effects

“…APP Swedish, which is adjacent to the β-secretase site in APP, is one of the well-known genetic mutations in familial Alzheimer's disease, resulting in increased total Aβ production [47][48][49]. Therefore, the research model for AD with an APP Swedish mutation is now widely used [50][51][52][53], and the H4SW cell line is called the AD in vitro model [20]. Moreover, Aβ accumulated in the brain of AD patients activates glia cells, which are known to eliminate Aβ and have neuroprotective effects [54][55][56][57].…”