Characterization of a 3xTg‐AD mouse model of Alzheimer's disease with the senescence accelerated mouse prone 8 (SAMP8) background

Abstract

No model fully recapitulates the neuropathology of Alzheimer's disease (AD). Although the triple-transgenic mouse model of AD (3xTg-AD) expresses Aβ plaques and tau-laden neurofibrillary tangles, as well as synaptic and behavioral deficits, it does not display frank neuronal loss. Because old age is the most important risk factor in AD, senescence-related interactions might be lacking to truly establish an AD-like environment. To investigate this hypothesis, we bred the 3xTg-AD mouse with the senescence-accelerated mouse prone 8 (SAMP8), a model of accelerated aging. We generated four groups of heterozygous mice with either the SAMP8 or SAMR1 (senescence-resistant-1) genotype, along with either the 3xTg-AD or non-transgenic (NonTg) genotype. Despite no differences among groups in total latency to escape the Barnes maze, a greater number of errors were noticed before entering the target hole in 19-month-old P8/3xTg-AD mice at day 5, compared to other groups. Postmortem analyses revealed increased cortical levels of phospho-tau (Thr231) in female P8/3xTg-AD mice (+277% vs. R1/3xTg-AD mice), without other tau-related changes. Female P8/3xTg-AD mice exhibited higher cortical soluble Aβ40 and Aβ42 concentrations (Aβ40, +85%; Aβ42, +35% vs. R1/3xTg-AD), whereas insoluble forms remained unchanged. Higher Aβ42 load coincided with increased astroglial activation in female P8/3xTg-AD mice, as measured with glial fibrillary acidic protein (GFAP) (+57% vs. R1/3xTg-AD mice). To probe neuronal degeneration, concentrations of neuronal nuclei (NeuN) were measured, but no differences were detected between groups. Altogether, the SAMP8 genotype had deleterious effects on spatial memory and exerted female-specific aggravation of AD neuropathology without overt neurodegeneration in 3xTg-AD mice.

Neuroligin-1 is altered in the hippocampus of Alzheimer’s disease patients and mouse models, and modulates the toxicity of amyloid-beta oligomers

“…Indeed, decreased NLGN1 was found at 4 months, an age at which cognitive symptoms are just starting to manifest and have been attributed to intraneuronal Aβ 57 . This model generally shows signs of neuronal death, human Aβ precursor protein (hAPP) deregulation, and Tau pathology later in life 42,60,61 , but these may all contribute to NLGN1 decrease together with alterations in Preselinin-1 in this model. The observation that only the females show this early decrease likely resides in the worst pathology observed in 3xTg-AD females in comparison to 3xTg-AD males.…”

“…The observation that only the females show this early decrease likely resides in the worst pathology observed in 3xTg-AD females in comparison to 3xTg-AD males. Indeed, 3xTg-AD females have repeatedly been reported to have, in particular, higher hAPP and Aβ levels than males 60,62,63 . Alternatively, a compensatory mechanism linked to the encoding of other NLGNs by sex chromosomes 64,65 , could also contribute to the sex-dependent decrease in NLGN1.…”

Sodium hydrosulfide alleviates dexamethasone‑induced cell senescence and dysfunction through targeting the miR‑22/sirt1 pathway in osteoblastic MC3T3‑E1 cells

“…An accumulating number of studies have suggested that cell senescence exerts a dominant role in a wide variety of diseases, including hepatocarcinogenesis (32), intervertebral disc degeneration (33), diabetic nephropathy (34), diabetic cardiomyopathy (35), Parkinson's disease (36) and Alzheimer's disease (37). Additionally, the crucial role of cell senescence in the development of osteoporosis has also been widely recognized (38,39).…”

Role of Kalirin and mouse strain in retention of spatial memory training in an Alzheimer’s disease model mouse line

“…The Morris Water Maze has been used more often than the Barnes Maze, which we utilized because it is less stressful (Barnes, 1979;Gawel et al, 2019;Hunsberger et al, 2014;Illouzm et al, 2016;Paul et al, 2009;Rosenfeld and Ferguson, 2014;Stover et al, 2015;Suzuki and Imayoshi, 2017;Varodayan et al, 2018). Using the Barnes Maze to compare nontransgenic and 3xTG-H mice at various ages, some studies revealed deficits in age-matched 3xTG-H mice (Fertan et al, 2019;Vandal et al, 2014), while others showed no consistent differences by genotype (Stover et al, 2015;Virgili et al, 2018). Comparing 3xTG-H mice with C57 controls, Aloni et al reported no difference in Barnes Maze performance (Aloni et al, 2019), in agreement with our results for naïve mice (Fig.…”