Behavioral testing affects the phenotypic expression of APOE ε3 and APOE ε4 in targeted replacement mice and reduces the differences between them

Abstract

Apolipoprotein E4 ( APOE ε4) is the most prevalent genetic risk factor for Alzheimer's disease (AD). Targeted replacement mice that express either APOE ε4 or its AD benign isoform, APOE ε3, are used extensively in behavioral, biochemical, and physiological studies directed at assessing the phenotypic effects of APOE ε4 and at unraveling the mechanisms underlying them. Such experiments often involve pursuing biochemical and behavioral measurements on the same cohort of mice. In view of the possible cross-talk interactions between brain parameters and cognitive performance, we presently investigated the extent to which the phenotypic expression of APOE ε4 and APOE ε4 in targeted replacement mice is affected by behavioral testing. This was performed using young, naïve APOE ε4 and APOE ε3 mice in which the levels of distinct brain parameters are affected by the APOE genotype (e.g., elevated levels of amyloid beta [Aβ] and hyperphosphorylated tau and reduced levels of vesicular glutamate transporter (VGLUT) in hippocampal neurons of APOE ε4 mice). These mice were exposed to a fear-conditioning paradigm, and the resulting effects on the brain parameters were examined. The results obtained revealed that the levels of Aβ, hyperphosphorylated tau, VGluT, and doublecortin of the APOE ε4 and APOE ε3 mice were markedly affected following the exposure of APOE ε4 and APOE ε3 mice to the fear-conditioning paradigm such that the isoform-specific effects of APOE ε4 on these parameters were greatly diminished. The finding that behavioral testing affects the APOE ε3 and APOE ε4 phenotypes and masks the differences between them has important theoretical and practical implications and suggests that the assessment of brain and behavioral parameters should be performed using different cohorts.

Apolipoprotein E regulates the maturation of injury-induced adult-born hippocampal neurons following traumatic brain injury

“…Together, these previous findings may help to explain the cognitive impairments exhibited by mice lacking ApoE or expressing ApoE4 particularly in spatial learning/memory and in olfactory memory, two neurogenic-dependent behaviors [63][64][65][66][67][68][69][70][71]. Although it remains unclear whether recovery from injuries such as TBI is dependent on neurogenesis in general and ApoE state in particular, the present study adds needed insight into a potential mechanism linking the two.…”

ApoE Regulates the Development of Adult Newborn Hippocampal Neurons

“…Hence, it is not surprising that impairments in performance in hippocampus-dependent behavioral tasks in mice deficient in ApoE or ones carrying the human ApoE4 are observed. Several studies have demonstrated that the presence of human ApoE4 or the absence of rodent ApoE impaired odor memory, Morris water maze task, and contextual fear-conditioning tasks ( Masliah et al, 1997 ; Grootendorst et al, 2001 ; Peister et al, 2006 ; Rodriguez et al, 2013 ; Salomon-Zimri et al, 2015 ; Peng et al, 2017 ; East et al, 2018 ). Further studies are required to determine the electrophysiology of newborn neurons under such genetic backgrounds to see whether they mimic the deficits in behavioral performance.…”

Alzheimer’s disease: A matter of blood–brain barrier dysfunction?

“…Similarly, genetic inhibition of the CypA–MMP-9 pathway at the BBB reversed neurodegenerative changes in Apoe −/− mice ( Bell et al, 2012 ). Because Apoe −/− ( Raber et al, 1998 ; Bell et al, 2012 ; Lane-Donovan et al, 2016 ) and APOE4 transgenic mice ( Bell et al, 2012 ; Salomon-Zimri et al, 2014 , 2015 ; Liu et al, 2015 ) develop behavioral deficits at 4–6 mo of age after BBB breakdown, collectively, these findings suggest that BBB breakdown ( Table 2 ) not only contributes to neuronal changes in these models but also is an important therapeutic target.…”