Neurokinin3 receptor as a target to predict and improve learning and memory in the aged organism

Abstract

Impaired learning and memory performance is often found in aging as an early sign of dementia. It is associated with neuronal loss and reduced functioning of cholinergic networks. Here we present evidence that the neurokinin3 receptors (NK3-R) and their influence on acetylcholine (ACh) release may represent a crucial mechanism that underlies age-related deficits in learning and memory. Repeated pharmacological stimulation of NK3-R in aged rats was found to improve learning in the water maze and in object-place recognition. This treatment also enhanced in vivo acetylcholinergic activity in the frontal cortex, hippocampus, and amygdala but reduced NK3-R mRNA expression in the hippocampus. Furthermore, NK3-R agonism incurred a significantly higher increase in ACh levels in aged animals that showed superior learning than in those that were most deficient in learning. Our findings suggest that the induced activation of ACh, rather than basal ACh activity, is associated with superior learning in the aged. To test whether natural variation in NK3-R function also determines learning and memory performance in aged humans, we investigated 209 elderly patients with cognitive impairments. We found that of the 15 analyzed single single-nucleotide ploymorphism (SNPs) of the NK3-R-coding gene, TACR3, the rs2765 SNP predicted the degree of impairment of learning and memory in these patients. This relationship could be partially explained by a reduced right hippocampus volume in a subsample of 111 tested dementia patients. These data indicate the NK3-R as an important target to predict and improve learning and memory performance in the aged organism. senktide | in vivo microdialysis H umans exhibit a decline in cognitive capacity with age, which may progressively lead to dementia (1). Age-dependent morphological and physiological changes within the cholinergic system of the brain have been described as a major mechanism underlying impairments of learning and memory (2, 3). Numerous studies in aged rats have revealed that a degeneration of cholinergic neurons in the basal forebrain is associated with learning and >memory deficits (4). Likewise, the consistent correlations found between cholinergic degeneration and cognitive impairments indicate a high correspondence between acetylcholinergic activity and the magnitude of cognitive decline (4-6). This relationship has also been shown in patients with Alzheimer's disease (7,8).The neuropeptide neurokinins (NKs) substance P, neurokinin A, neurokinin B (NK-B), neuropeptide K, neuropeptide γ, and hemokinin 1 bind to the three known NK-receptors (NK3-R) (NK1-, NK2-, and NK3-R) with different degrees of affinity, whereby NK-B is the preferred ligand to NK3-R (9). NK3-Rs are widespread in the brain, including areas that are implicated in processes governing learning and memory such as the hippocampus, frontal cortex (FC), and medial septum (10, 11). There is a close interaction between NK3-R and the cholinergic system. NK3-R are localized on cholinacetyltransferase-containing neurons in ...

Bamboo leaf extract improves spatial learning ability in a rat model with senile dementia

“…An ideal animal model should exhibit all AD features in animals (Neha et al, 2014). Aging animals are commonly employed in AD drug development because they mimic not only the morphological characteristics (Erickson and Barnes, 2003;Gupta et al, 2013) but also the pathophysiology (de Souza Silva et al, 2013) of human Alzheimer's disease. Chronic administration of D-gal induces changes that resemble natural aging in rodents, including neurodegeneration (Ho et al, 2003;Zhang et al, 2005) and cognitive dysfunction (Cui et al, 2006;Wang et al, 2013), and thus becomes a routinely used method to induce aging in rodents (Wei al., 2005).…”

Association of a neurokinin 3 receptor polymorphism with the anterior basal forebrain

“…Based on the evidence from a previous study in older adults with MCI and AD dementia (de Souza Silva et al, 2013), we additionally determined the association of the rs2765 SNP with hippocampus volumes. For comparison, we determined the association of ApoE ε4 genotype with regional brain volumes.…”

“…A previous study had shown that the rs2765 SNP of the TACR3 gene was associated with right hemispheric hippocampus volume in 111 participants with MCI or AD dementia (de Souza Silva et al, 2013). This previous study had assessed hippocampus volume as a brain region with dense cholinergic innervation and a target area of cholinergic activation mediated through the medial septum in response to activation of the NK3 receptor (Schäble et al, 2012).…”

“…A study in 111 older adults with mild cognitive impairment (MCI) or Alzheimer's disease (AD) dementia has shown an association of the rs2765 single-nucleotide polymorphism (SNP) of the NK3 receptorecoding gene TACR3 with smaller right hippocampus volume (de Souza Silva et al, 2013). This association has been interpreted as an indirect evidence for the implication of the rs2765 SNP in the regulation of cholinergic function in the human brain.…”

“…We assessed both hippocampus volume, using a recently established harmonized measurement protocol (Frisoni et al, 2015), and volumes of the cholinergic BF, using masks from postmortem magnetic resonance imaging (MRI) and histology data (Kilimann et al, 2014;Teipel et al, 2005). Based on the notion that the SNP in the NK3 receptor would be associated with cholinergic system integrity (Chen et al, 2001) and that BF volumetry would be a more direct measure of cholinergic system integrity than the previously used hippocampus volume (de Souza Silva et al, 2013), we hypothesized that the rs2765 SNP would be associated with BF volume as marker of cholinergic neuronal integrity and modulate the effect of age on this brain region. Such findings would render the SNP of the NK3 receptorecoding gene TACR3 a potential risk marker for neurodegenerative changes associated with aging.…”