Restoration of dopamine release deficits during object recognition memory acquisition attenuates cognitive impairment in a triple transgenic mice model of Alzheimer's disease

Abstract

Previous findings indicate that the acquisition and consolidation of recognition memory involves dopaminergic activity. Although dopamine deregulation has been observed in Alzheimer's disease (AD) patients, the dysfunction of this neurotransmitter has not been investigated in animal models of AD. The aim of this study was to assess, by in vivo microdialysis, cortical and hippocampal dopamine, norepinephrine, and glutamate release during the acquisition of object recognition memory (ORM) in 5-and 10-mo-old triple-transgenic Alzheimer's disease mice (3xTg-AD) and to relate the extracellular changes to 24-h memory performance. Five-and 10-mo-old wild-type mice and 5-mo-old 3xTg-AD showed significant cortical but not hippocampal dopamine increase during object exploration. On a 24-h ORM test, these three groups displayed significant ORM. In contrast, 10-mo-old 3xTg-AD mice showed impaired dopamine release in the insular cortex during ORM acquisition, as well as significant impairment in ORM. In addition, cortical administration of a dopamine reuptake blocker produced an increase of dopamine levels in the 10-mo-old 3xTg-AD mice and attenuated the memory impairment. These data suggest that activation of the dopaminergic system in the insular cortex is involved in object recognition memory, and that dysfunction of this system contributes to the age-related decline in cognitive functioning of the 3xTg-AD mice.Alzheimer's disease (AD) is an age-related and progressive degenerative disorder generally characterized by two neuropathological features: deposits of amyloid-beta (Ab) peptides and neurofibrillary tangles, formed by the hyperphosphorylated microtubulebinding protein tau (Selkoe 2001). These neuropathological features are generally prominent in learning and memory-related brain regions, including the hippocampus, amygdala, and neocortex (Braak and Braak 1991;Nicholson et al. 2010). Because these pathologies are related to synaptic dysfunction leading to neurotransmitter deregulation including acetylcholine deficiency (Davis et al. 1999), several pharmacological therapies for AD focus on the restoration or modulation of cholinergic neurotransmission by acetylcholinesterase inhibitors and muscarinic agonists (Caccamo et al. 2009;Galluzzi et al. 2010). However, there is also evidence that these treatments may increase extracellular levels of dopamine (DA) (Shearman et al. 2006;Preda et al. 2008), suggesting that DA increase may contribute to the therapeutic effect. The possibility that the dopaminergic system may be involved in AD is suggested by evidence of decreased DA levels assessed in post-mortem brain tissue of AD patients (Winblad et al. 1985;Nazarali and Reynolds 1992;Storga et al. 1996), as well as changes in DA receptor distribution and density in several brain structures of the temporal lobe (Joyce et al. 1993(Joyce et al. , 1998Kemppainen et al. 2003;Kumar and Patel 2007).Transgenic models of AD are widely used to study the role of Ab accumulation and tau tangles in the cognitive alterations characteristi...

“Is dopamine involved in Alzheimer's disease?”

“…Indeed, experimental data from transgenic mice AD showed how the DA-ergic pathology and amyloid deposition are closely related, suggesting a causative role for amyloid on dopamine dysfunction (Perez et al, 2005). Moreover, the restoration of DA transmission was demonstrated to play a role in memory and learning in a mouse model of AD, strengthening the central role of DA in cognitive tasks (Ambrée et al, 2009; Guzmán-Ramos et al, 2012). This has been recently associated to a demonstrated protective role, having DA an anti-amyloidogenic and anti-oxidant effects in mice brain (Himeno et al, 2011).…”

Comparison of Efficacy of Preventive and Therapeutic Vaccines Targeting the N Terminus of β-Amyloid in an Animal Model of Alzheimer’s Disease

“…The novel object and novel place recognition tasks are believed to be primarily dependent on both cortex and hippocampus, although the contributions of these two regions are distinct and dissociable. [54][55][56][57] Therefore, we analyzed AD-like pathology in the cortical and hippocampal regions of vaccinated mice with and without memory Th cells and control non-vaccinated mice. We observed that immunization with EV was effective in reducing AD-like pathology in the cortex but not in the hippocampus, and this effect depended on pre-existing Th cells ( Figure 6).…”

“…[54][55][56][57] Accordingly, as a pre-clinical test of the therapeutic efficacy of EV vaccination, we studied neuropathological changes in the brains of aged Tg2576 mice (average 15-15.5 months old) possessing or not possessing the pre-existing memory Th cells prior to vaccinations. We tested numbers of 6E10 (diffuse and cored)-and ThS (cored)-positive plaques in the cortex and hippocampus of vaccinated mice with or without memory Th cells and the control adjuvant-only injected mice ( Figure 6).…”

Translating the N-methyl-d-aspartate receptor antagonist model of schizophrenia to treatments for cognitive impairment in schizophrenia

“…Increased cortical DA release.has been demonstrated during a variety of cognitive behaviours in rodents, including cognitive behaviours (Giovannini et al, 1998;Phillips et al, 2004;Ihalainen et al, 2010;Guzmán-Ramos et al, 2012;Stanley et al, 2012) and in primates in a working memory task (Watanabe et al, 1997).…”