PDE10A
cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A (EC 3.1.4.17) (EC 3.1.4.35)
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Deficits in brain function that are associated with aging and age-related diseases benefit very little from currently available therapies, suggesting a better understanding of the underlying molecular mechanisms is needed to develop improved drugs. Here, we review the literature to test the hypothesis that a break down in cyclic nucleotide signaling at the level of synthesis, execution, and/or degradation may contribute to these deficits. A number of findings have been reported in both the human and animal model literature that point to brain region-specific changes in Galphas (a.k.a. Gαs or Gsα), adenylyl cyclase, 3',5'-adenosine monophosphate (cAMP) levels, protein kinase A (PKA), cAMP response element binding protein (CREB), exchange protein activated by cAMP (Epac), hyperpolarization-activated cyclic nucleotide-gated ion channels (HCNs), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), soluble and particulate guanylyl cyclase, 3',5'-guanosine monophosphate (cGMP), protein kinase G (PKG) and phosphodiesterases (PDEs). Among the most reproducible findings are 1) elevated circulating ANP and BNP levels being associated with cognitive dysfunction or dementia independent of cardiovascular effects, 2) reduced basal and/or NMDA-stimulated cGMP levels in brain with aging or Alzheimer's disease (AD), 3) reduced adenylyl cyclase activity in hippocampus and specific cortical regions with aging or AD, 4) reduced expression/activity of PKA in temporal cortex and hippocampus with AD, 5) reduced phosphorylation of CREB in hippocampus with aging or AD, 6) reduced expression/activity of the PDE4 family in brain with aging, 7) reduced expression of PDE10A in the striatum with Huntington's disease (HD) or Parkinson's disease, and 8) beneficial effects of select PDE inhibitors, particularly PDE10 inhibitors in HD models and PDE4 and PDE5 inhibitors in aging and AD models. Although these findings generally point to a reduction in cyclic nucleotide signaling being associated with aging and age-related diseases, there are exceptions. In particular, there is evidence for increased cAMP signaling specifically in aged prefrontal cortex, AD cerebral vessels, and PD hippocampus. Thus, if cyclic nucleotide signaling is going to be targeted effectively for therapeutic gain, it will have to be manipulated in a brain region-specific manner.
MeSH Terms
- Adenylyl Cyclases
- Aging
- Atrial Natriuretic Factor
- Brain
- Cyclic AMP
- Cyclic AMP Response Element-Binding Protein
- Cyclic AMP-Dependent Protein Kinases
- Cyclic GMP
- Cyclic GMP-Dependent Protein Kinases
- Gene Expression Regulation
- Guanine Nucleotide Exchange Factors
- Heterotrimeric GTP-Binding Proteins
- Humans
- Natriuretic Peptide, Brain
- Neurodegenerative Diseases
- Signal Transduction
Keywords
- Age-related cognitive decline
- Aging
- Alzheimer's disease
- Cerebellum
- Cortex
- Cyclic nucleotides
- Hippocampus
- Huntington's disease
- Memory
- Mild cognitive impairment
- PDE1
- PDE11
- PDE3
- PDE7
- PDE8
- Parkinson's Disease
- Phosphodiesterase
- Striatum
- cAMP
- cGMP
Phosphodiesterase 10A enzyme (PDE10A) is an important striatal target that has been shown to be affected in patients with neurodegenerative disorders, particularly Huntington´s disease (HD). PDE10A is expressed on striatal neurones in basal ganglia where other known molecular targets are enriched such as dopamine D receptors (D R). The aim of this study was to examine the availability of PDE10A enzyme in relation with age and gender and to compare those changes with those related to D R and volumes in different regions of the basal ganglia. As a secondary objective we examined the relative distribution of D R and PDE10A enzyme in the striatum and globus pallidus. Forty control subjects (20F/20M; age: 44±11y, age range 27-69) from an ongoing positron emission tomography (PET) study in HD gene expansion carriers were included. Subjects were examined with PET using the high-resolution research tomograph (HRRT) and with 3T magnetic resonance imaging (MRI). The PDE10A radioligand F-MNI-659 and D R radioligand C-raclopride were used. The outcome measure was the binding potential (BP ) estimated with the two-tissue compartment model ( F-MNI-659) and the simplified reference tissue model ( C-raclopride) using the cerebellum as reference region. The PET data were corrected for partial volume effects. In the striatum, PDE10A availability showed a significant age-related decline that was larger compared to the age-related decline of D R availability and to the age-related decline of volumes measured with MRI. In the globus pallidus, a less pronounced decline of PDE10A availability was observed, whereas D R availability and volumes seemed to be rather stable with aging. The distribution of the PDE10A enzyme was different from the distribution of D R, with higher availability in the globus pallidus. These results indicate that aging is associated with a considerable physiological reduction of the availability of PDE10A enzyme in the striatum. Moreover as result of the analysis, in the striatum for both the molecular targets, we observed a gender effect with higher BP the female group.
MeSH Terms
- Adult
- Aged
- Aging
- Basal Ganglia
- Female
- Humans
- Image Enhancement
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Phosphoric Diester Hydrolases
- Phthalimides
- Positron-Emission Tomography
- Quinazolinones
- Raclopride
- Receptors, Dopamine D2
- Receptors, Dopamine D3
3',5'-cyclic nucleotide phosphodiesterases (PDEs) are the only known enzymes to compartmentalize cAMP and cGMP, yet little is known about how PDEs are dynamically regulated across the lifespan. We mapped mRNA expression of all 21 PDE isoforms in the adult rat and mouse central nervous system (CNS) using quantitative polymerase chain reaction (qPCR) and in situ hybridization to assess conservation across species. We also compared PDE mRNA and protein in the brains of old (26 months) versus young (5 months) Sprague-Dawley rats, with select experiments replicated in old (9 months) versus young (2 months) BALB/cJ mice. We show that each PDE isoform exhibits a unique expression pattern across the brain that is highly conserved between rats, mice, and humans. PDE1B, PDE1C, PDE2A, PDE4A, PDE4D, PDE5A, PDE7A, PDE8A, PDE8B, PDE10A, and PDE11A showed an age-related increase or decrease in mRNA expression in at least 1 of the 4 brain regions examined (hippocampus, cortex, striatum, and cerebellum). In contrast, mRNA expression of PDE1A, PDE3A, PDE3B, PDE4B, PDE7A, PDE7B, and PDE9A did not change with age. Age-related increases in PDE11A4, PDE8A3, PDE8A4/5, and PDE1C1 protein expression were confirmed in hippocampus of old versus young rodents, as were age-related increases in PDE8A3 protein expression in the striatum. Age-related changes in PDE expression appear to have functional consequences as, relative to young rats, the hippocampi of old rats demonstrated strikingly decreased phosphorylation of GluR1, CaMKIIα, and CaMKIIβ, decreased expression of the transmembrane AMPA regulatory proteins γ2 (a.k.a. stargazin) and γ8, and increased trimethylation of H3K27. Interestingly, expression of PDE11A4, PDE8A4/5, PDE8A3, and PDE1C1 correlate with these functional endpoints in young but not old rats, suggesting that aging is not only associated with a change in PDE expression but also a change in PDE compartmentalization.
MeSH Terms
- 3',5'-Cyclic-AMP Phosphodiesterases
- Aging
- Animals
- Brain
- Cerebellum
- Cerebral Cortex
- Corpus Striatum
- Gene Expression Regulation, Enzymologic
- Hippocampus
- Male
- Mice
- Mice, Inbred BALB C
- Protein Isoforms
- RNA, Messenger
- Rats
- Rats, Sprague-Dawley
Keywords
- Alzheimer's disease
- Model
- Neuron
- PDE11
- PDE8
- Tissue distribution