Object recognition memory and BDNF expression are reduced in young TgCRND8 mice

Abstract

The TgCRND8 mouse model of Alzheimer's disease exhibits progressive cortical and hippocampal β-amyloid accumulation, resulting in plaque pathology and spatial memory impairment by 3 months of age. We tested whether TgCRND8 cognitive function is disrupted prior to the appearance of macroscopic plaques in an object recognition task. We found profound deficits in 8-week-old mice. Animals this age were not impaired on the Morris water maze task. TgCRND8 and littermate controls did not differ in their duration of object exploration or optokinetic responses. Thus, visual and motor dysfunction did not confound the phenotype. Object memory deficits point to the frontal cortex and hippocampus as early targets of functional disruption. Indeed, we observed altered levels of brain-derived neurotrophic factor (BDNF) messenger ribonucleic acid (mRNA) in these brain regions of preplaque TgCRND8 mice. Our findings suggest that object recognition provides an early index of cognitive impairment associated with amyloid exposure and reduced brain-derived neurotrophic factor expression in the TgCRND8 mouse.

Reduced Tissue Levels of Noradrenaline Are Associated with Behavioral Phenotypes of the TgCRND8 Mouse Model of Alzheimer's Disease

“…How Ab leads to neuronal dysfunction and behavioral abnormalities is unknown. We reported previously that TgCRND8 mice develop object memory deficits by 8 weeks of age, before frank plaque pathology but coincident with a twofold increase in Ab levels and reduced BDNF mRNA in the hippocampus and frontal cortex (Francis et al, 2012). We argued that decreased BDNF expression contributes to the functional disruption of these brain regions that are first targeted by amyloid.…”

“…These mice exhibit deficits in memory and brain-derived neurotrophic factor (BDNF) mRNA as early as 2 months (Francis et al, 2012), significant plaque loads within hippocampus and cortex by 3 months (Chishti et al, 2001) and cholinergic dysfunction by 7 months of age (Bellucci et al, 2006). We now report that reductions in tissue NA precede the appearance of plaques and cholinergic dysfunction and strongly contribute to behavioral phenotypes and decreased BDNF expression.…”

“…This regimen ensured that experimentally naive mice received 2 weeks of continuous drug treatment before assessment and were sufficiently habituated for measures of behavior. The object recognition test was conducted on treatment day 19, as described previously (Francis et al, 2012). Each mouse was exposed for 10 min to a LEGO construct (LEGO Group, Billund, Denmark) and a Hot Wheels car (Mattel, El Segundo, CA, USA).…”

7,8-Dihydroxyflavone, a Small-Molecule TrkB Agonist, Reverses Memory Deficits and BACE1 Elevation in a Mouse Model of Alzheimer's Disease

“…A growing body of evidence indicates that BDNF levels are decreased in brains of AD patients (Hu and Russek, 2008;Peng et al, 2005;Zuccato and Cattaneo, 2009) and APP transgenic mice (Francis et al, 2010;Peng et al, 2009). We first characterized changes in BDNF levels in the 5XFAD transgenic mouse model at different ages ranging from 3 to 18 months (Figure 1).…”

BDNF controls object recognition memory reconsolidation

“…Brain-Derived Neurotrophic Factor (BDNF) is a member of the neurotrophin family of growth factors essential for synapse formation and maintenance (Cowansage, LeDoux, & Monfils, 2010;Panja & Bramham, 2014). In the rat hippocampus, BDNF mediates spatial and recognition memory formation (Francis et al, 2012;Furini et al, 2010;Harvey et al, 2008;Petzold, Psotta, Brigadski, Endres, & Lessmann, 2015;Silhol, Arancibia, Maurice, & Tapia-Arancibia, 2007) and is sufficient for reconsolidation of fear extinction . Thus, we wondered whether this neurotrophin also maintains the recognition memory trace upon reactivation.…”