Evidence for Early Cognitive Impairment Related to Frontal Cortex in the 5XFAD Mouse Model of Alzheimer's Disease

Abstract

The frontal cortex is a brain structure that plays an important role in cognition and is known to be affected in Alzheimer's disease (AD) in humans. Over the past years, transgenic mouse models have been generated to recapitulate the main features of this disease, including cognitive impairments. This study investigates frontal cortex dependent learning abilities in one of the most early-onset transgenic murine model of AD, the 5XFAD mice. We compared frontal performance of 2-, 4-, and 6-month-old 5XFAD mice with their wild-type littermates using a newly developed automated device, the olfactory H-maze, in which mice have to discover three different rules consecutively according to the delayed reaction paradigm. We report early cognitive deficits related to frontal cortex appearing in 4-month-old 5XFAD mice before hippocampal-dependent learning and memory impairment, in relation with neuropathologic processes such as strong gliosis and emerging amyloid plaques. The present results demonstrate that the olfactory H-maze is a very sensitive and simple experimental paradigm that allows assessment of frontal functions in transgenic mice and should be useful to test pre-clinical therapeutic approaches to alter the course of AD.

Differential spatio-temporal regulation of MMPs in the 5xFAD mouse model of Alzheimer’s disease: evidence for a pro-amyloidogenic role of MT1-MMP

“…The same study suggested that the release of these MMPs by astrocytes contribute to Aβ degradation. Interestingly, despite the well-reported activation of microglial cells in 5xFAD mice (Oakley et al, 2006; Girard et al, 2013), neither MMP-2 nor MMP-9 seemed to be associated with these cells. In the case of MMP-9, its microglial upregulation has been previously associated with neurotoxic effects on hippocampal neurons (Rivera et al, 2002; Jourquin et al, 2003), indirectly suggesting that activated microglia in the 2- to 6-month old 5xFAD mice are involved in beneficial rather than detrimental processes.…”

“…5xFAD mice harbor three familial Alzheimer’s disease (FAD) mutations in the human APP 695 (Swedish K670N, M671L; Florida I716V and London V717I) and two mutations in the human presenilin-1 ( PSEN-1 ) (M146L, L286V) under the transcriptional control of the neuron-specific mouse Thy-1 promoter. These mice show over a 6- to 9-month period intracellular and extracellular accumulation of Aβ42, gliosis, synaptic demise, cognitive impairment and neuronal loss (Oakley et al, 2006; Ohno et al, 2007; Girard et al, 2013). Behavioral dysfunctions have been primarily described in 5xFAD females (Jawhar et al, 2012), which present a more prominent amyloid pathology than males.…”

“…Behavioral dysfunctions have been primarily described in 5xFAD females (Jawhar et al, 2012), which present a more prominent amyloid pathology than males. However, recent behavioral data obtained using olfactory-based tests, have uncovered subtle deficits of cortical- and hippocampal-dependent cognition in males as early as 4 months that are absent at 2 months and are more severe at 6 months (Girard et al, 2013, 2014). Another study has also highlighted hippocampal-dependent spatial memory deficits in 5-month-old 5xFAD males in the Morris water maze (Hongpaisan et al, 2011).…”

“…However, the evolution of MMPs expression from asymptomatic to symptomatic phases is unknown, and yet it may provide valuable insights on the role of these proteinases in AD. From previous work (Oakley et al, 2006; Jawhar et al, 2012; Giannoni et al, 2013; Girard et al, 2013), the 5xFAD mouse model of AD has been shown to recapitulate within the first 6 months of life asymptomatic, prodromal-like and symptomatic phases reminiscent of AD pathology. Accordingly, we have investigated the brain distribution of MMP-2, MMP-9 and MT1-MMP at 2, 4 and 6 months, each time point corresponding to these three phases, respectively.…”

Stimulation of 5-HT2C Receptors Improves Cognitive Deficits Induced by Human Tryptophan Hydroxylase 2 Loss of Function Mutation

“…Here we investigate the consequences of chronic 5-HT deficiency and pharmacological treatments on cognitive functions in R439H Tph2-KI mice with the automated H-maze (Del'Guidice et al, 2009;Girard et al, 2012). This behavioral test is a recently developed cognitive assay that involves a delayed reaction paradigm (Belhaoues et al, 2005), consisting in the consecutive discovery of three different rules: a delayed alternation task, a non-alternation task, and a delayed reversal task requiring a stronger mobilization of cognitive resources (Del'Guidice et al, 2009).…”