Possible Role of Dynorphins in Alzheimer's Disease and Age-Related Cognitive Deficits

Abstract

Background/Aims: Expression of dynorphin, an endogenous opioid peptide, increases with age and has been associated with cognitive deficits in rodents. Elevated dynorphin levels have been reported in postmortem samples from Alzheimer's disease (AD) patients, and prodynorphin (PDYN) gene polymorphisms might be linked to cognitive function in the elderly. Activation of κ-opioid receptors by dynorphins has been associated with stress-related memory impairments. Interestingly, these peptides can also modulate glutamate neurotransmission and may affect synaptic plasticity underlying memory formation. N-methyl-<smlcap>D</smlcap>-aspartate (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMPA) ionotropic glutamate receptor levels generally decrease with aging, and their function is impaired in AD. Methods: Here, we compared the impact of aging on ionotropic glutamate receptor levels in the hippocampal formation of wild-type (WT) and Pdyn knock-out (KO) mice. Results: We observed a significant reduction in GluR1 and GluR2 AMPA receptor subunits in the hippocampal formation of 18- to 25-month-old WT mice in comparison with 6-month-old mice. Conversely, the GluR1 protein level was maintained in old Pdyn KO mice, and the NMDA NR2B subunit level was increased by 42% when compared to old WT animals. Conclusions: These results suggest that elevated dynorphin expression occurring during aging and AD may mediate cognitive deficits by altering the glutamatergic system integrity.

Glutamatergic signaling and low prodynorphin expression are associated with intact memory and reduced anxiety in rat models of healthy aging

“…Activation of κ-opioid receptors (KOR), the main target of dynorphins, suppresses glutamate release (Simmons et al, 1994), and KOR activation mediates stress-induced memory deficits (Carey et al, 2009). Reduction of Pdyn gene expression protects old mice from cognitive impairments and anxious behaviors through upregulation of group 1 mGluR expression and function (Menard et al, 2013) and may favor AMPA GluR1 and NMDA NR2B expression in the aged brain (Menard et al, 2014). Both group 1 mGluR function and Homer 1 expression have been associated with stress-induced cognitive deficits (Tronson et al, 2010; Menard et al, 2013; Wagner et al, 2013), and anxious behaviors are exacerbated by aging in the mGluR5 −/− mice (Inta et al, 2013).…”

Glutamate presynaptic vesicular transporter and postsynaptic receptor levels correlate with spatial memory status in aging rat models

“…Western blot analysis was carried out on HAC homogenates (Menard and Quirion, 2012b;Menard et al, 2013Menard et al, , 2014aMenard et al, , 2014b or PSD aliquots (Menard and Quirion, 2012b) to assess receptor levels. Briefly, protein concentrations of homogenates and PSD preparations were first determined with the bicinchoninic acid protein assay kit (Pierce, Rockford, IL, USA).…”

“…Ten micrograms of protein from each sample was then loaded on denaturing NuPAGE Novex 4%e20% BiseTris gel (Invitrogen, Carlsbad, CA, USA) and subjected to SDS-PAGE. This concentration of protein is optimal for all antibodies tested as determined by serial dilutions of young rat HAC samples (Menard et al, 2014a). Proteins were transferred onto Hybond-C nitrocellulose membranes (Amersham Biosciences, Little Chalfont, UK) and incubated for 1 hour at room temperature in phosphate-buffered saline containing 0.05% Tween 20 (PBST) and 2% bovine serum albumin (BSA) to block nonspecific sites.…”

“…Following washes in Tris-buffered saline containing 0.05% Tween 20, bands corresponding to proteins were revealed with horseradish peroxidase-conjugated secondary antibody (1:10,000, Santa Cruz Biotechnology) and Western Lightning Chemiluminescence Reagent Plus (Perkin Elmer, Boston, MA, USA) on Kodak BioMax MS film (Amersham Biosciences). Nonspecific labeling was assessed by omitting the primary antibody and immunoreactive levels of b-actin served as the loading control (Menard and Quirion, 2012b;Menard et al, 2013Menard et al, , 2014aMenard et al, , 2014b. Relevant computer-generated images of the immunoblots were analyzed semiquantitatively by densitometry with a microcomputer imaging device (Imaging Research, MCID, St. Catharines, ON, Canada).…”

Signaling Pathways Relevant to Cognition-Enhancing Drug Targets

“…These results are in line with previous studies in which positive modulation of mGluR5 (Uslaner et al 2009;Reichel et al 2011;Fowler et al 2013) as well as norBNI treatment (Bilkei-Gorzo et al 2014) promoted memory formation. Conversely, mGluR5 antagonism impaired spatial memory of old Pdyn KO mice (Menard et al 2013b), suggesting that dynorphinergic and glutamatergic systems closely interact to establish memories in the aging brain (Menard et al 2013b(Menard et al , 2014a. Gene expression profiling reveals increased Pdyn expression in the hippocampus of amnesic scopolamine-treated rats (Brouillette et al 2007), raising the possibility of complex interactions between these systems in cognitive functions.…”