Long-term prevention of Alzheimer's disease-like behavioral deficits in PDAPP mice carrying a mutation in Asp664

Abstract

The deficits of Alzheimer's disease (AD) are believed to result, at least in part, from neurotoxicity of β-amyloid (Aβ), a set of 38-43 amino acid fragments derived from the β-amyloid precursor protein (APP). In addition, APP generates the APP-C31 and Jcasp toxic fragments intracellularly by cleavage at Asp664. We reported that mutation of Asp664 to A in a FAD-human APP transgene prevented AD-like deficits but did not affect Aβ production or deposition in PDAPP mice, arguing that D664A plays a crucial role in the generation of AD-like deficits. Whether D664A simply delays or completely prevents AD-like deficits, however, remained undefined. To address this question, we performed behavioral studies longitudinally on a pretrained mouse cohort at 9 and 13 months of age. While behavioral deficits were present in PDAPP mice, performance of Tg PDAPP(D664A) mice was not significantly different from non-Tg littermates' across all ages tested. Moreover, aberrant patterns in non-cognitive components of behavior in PDAPP mice were ameliorated in PDAPP(D664A) animals as well. A trend towards poorer retention at 9 mo and poorer learning at 13 mo that did not reach statistical significance was observed in PDAPP(D664A) mice. These results support and extend recent studies showing that cleavage of APP at Asp664 (or protein-protein interactions dependent on Asp664) is a crucial event in the generation of AD-like deficits in PDAPP mice. Our results thus further demonstrate that the D664A mutation either completely precludes, or markedly delays (beyond 13 mo) the appearance of AD-like deficits in this mouse model of AD.

Cognitive phenotyping of amyloid precursor protein transgenic J20 mice

“…Transgenic and nontransgenic mice exhibited a similar ability to learn the location of the food reward over a number of days. Earlier studies described a deficit in MWM training for transgenic mice in the hidden version of the test paradigm [14][15][16][17][18]28], whereas task acquisition in the cued version of the MWM was not always impaired [16]. Studies by Galvan and Harris confirmed that test age and pre-test experience play a significant role in the MWM performance of J20 mice [14,28].…”

“…swimming at speeds lower than 0.025m/s) and to thigmotactic swimming (i.e. swim paths restricted to 10 cm from the wall) compared to non-transgenic mice, which are both confounding factors for MWM testing [14]. Thus, we decided to test J20 mice in a "dry version" of the MWM to circumvent the disadvantages of the MWM.…”

“…Earlier studies described a deficit in MWM training for transgenic mice in the hidden version of the test paradigm [14][15][16][17][18]28], whereas task acquisition in the cued version of the MWM was not always impaired [16]. Studies by Galvan and Harris confirmed that test age and pre-test experience play a significant role in the MWM performance of J20 mice [14,28]. Importantly, similar to what has been described in studies using the hidden version of the MWM paradigm, hAPPSwInd transgenic mice of our study displayed a significant cognitive deficit in the probe trial, during which no significant preference for the target zone was detectable.…”

“…Importantly, thigmotactic swimming and floating behaviour may confound the MWM performance of hAPPSwInd transgenic mice [14]. Some of the other cognitive impairments reported are inconsistent across studies [14][15][16][17][18]. Thus, our study aimed to clarify the nature of the cognitive deficits of J20 mice by testing transgenic and non-transgenic control animals in contextual and cued fear conditioning, the cheeseboard task [i.e.…”

Chronic Rapamycin Restores Brain Vascular Integrity and Function Through NO Synthase Activation and Improves Memory in Symptomatic Mice Modeling Alzheimer’s Disease

“…(B) Spatial memory is restored by rapamycin treatment. While memory in control-fed AD mice was impaired 35,45,46 (P values as indicated, Tukey's test applied to a significant effect of genotype and treatment (Po0.0001), one-way ANOVA), memory in rapamycin-fed AD mice was indistinguishable from WT littermate groups and was significantly improved compared with control-fed AD mice Experiments (ARRIVE) guidelines as described by Kilkenny et al 44 have been followed in the preparation of this manuscript.…”