Intact cannabinoid CB1 receptors in the Alzheimer's disease cortex
Research highlights
▶ Cannabinoid CB1 receptors are preserved in various cortical regions of AD. ▶ CB1 receptor immunoreactivity correlates with pre-death cognitive scores in AD. ▶ Intact CB1 receptors may be associated with better cognitive function in AD. ▶ CB1 receptors should be further assessed as therapeutic targets in AD.
Introduction
Alzheimer's disease (AD) represents the bulk of neurodegenerative dementia as well as associated healthcare costs in both developed and developing regions of the world (DeKosky and Orgogozo, 2001, Wimo et al., 2006, Kalaria et al., 2008). Neuropathologic features of AD include intercellular β-amyloid (Aβ)-containing neuritic plaques as well as intracellular neurofibrillary tangles in multiple regions of the cortex (Selkoe and Podlisny, 2002). Another salient feature of AD is the perturbation of various neurotransmitter systems and concomitant alterations of associated receptors and synthetic enzymes. For example, AD has been found to manifest neuronal degeneration in the basal forebrain cholinergic system and deficits of choline acetyltransferase (Whitehouse et al., 1982, Wilcock et al., 1983), together with alterations of muscarinic and nicotinic acetylcholine receptors (Nordberg et al., 1992, Flynn et al., 1995, Court et al., 2001, Lai et al., 2001). Besides the cholinergic system, another neurotransmitter system known to be affected in AD is the glutamatergic system which comprises the majority of excitatory pyramidal neurons throughout the neocortex and may mediate the excitotoxicity of AD (Francis, 1996, Francis, 2006, Olney et al., 1997). These findings supported the development of acetylcholinesterase inhibitors (AChEIs) and memantine, a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist, in dementia pharmacotherapy (Geerts and Grossberg, 2006, Thomas and Grossberg, 2009). However, such therapeutics have proven to be of limited benefit. Moreover, AChEI administration results in side effects such as nausea, dizziness and diarrhoea (Birks, 2006), while memantine is generally prescribed only for severe AD and has limited pro-cognitive effects (Areosa et al., 2005). Therefore, there is a need to identify and study other potential targets for AD pharmacotherapy.
Recently, the endocannabinoid system has attracted much interest as a novel target for AD and other neurodegenerative diseases due to potentially neuroprotective, anti-inflammatory and neurotrophic effects of certain cannabinoids (Campbell and Gowran, 2007, Basavarajappa et al., 2009). Researchers have shown that certain marijuana components prevent AChE-induced Aβ aggregation and competitively inhibit AChE (Eubanks et al., 2006) as well as Aβ-induced tau hyperphosphorylation in vitro (Esposito et al., 2006), and may therefore amplify the therapeutic effects of AChEIs and have other disease-modifying effects. Neurochemically, the endocannabinoid system plays a significant role in regulating cholinergic and glutamatergic neurotransmission. For example, the Gαi-coupled, presynaptic CB1 receptor is widely expressed in neurons throughout the brain, including neocortex, hippocampus, and cerebellum (Herkenham et al., 1991, Tsou et al., 1998, Kawamura et al., 2006), where it mediates fast retrograde signaling of endogenous cannabinoids to inhibit further release of neurotransmitters in depolarized neurons (Kreitzer and Regehr, 2001, Wilson and Nicoll, 2001, Ohno-Shosaku et al., 2002). CB1 receptors are also the major cannabinoid receptors at cholinergic, glutamatergic and GABAergic synapses in the hippocampus, where they suppress the induction of both long term potentiation (LTP) as well as long term depression (LTD) (Sullivan, 2000). Interestingly, deletion of the CB1 gene in rodents results in improved learning, putatively through enhancing cholinergic neurotransmission (Degroot et al., 2005). This supports the proposal of utilizing CB1 receptor antagonists as potential novel therapeutics in AD (Basavarajappa et al., 2009). However, the status of CB1 receptors in the AD brain remains unclear, with findings of decreased CB1 receptor immunoreactivity and ligand binding contrasted with unchanged mRNA levels (Westlake et al., 1994, Ramírez et al., 2005), while another group found no changes (Benito et al., 2003). The relationship between CB1 receptors and cognitive impairment in AD is also unknown. In this study, we investigated CB1 receptors in the cortex of a prospectively assessed cohort of AD patients.
Section snippets
Patients, clinical and neuropathologic data
Brain tissues were obtained from the Oxford Project to Investigate Memory and Ageing (OPTIMA, see http://www.medsci.ox.ac.uk/optima). Subjects for this study constituted a randomly selected subset of the participants who had postmortem follow-up, now part of the Thomas Willis Oxford Brain Collection within the Brains for Dementia Research Initiative (BDR). The majority of subjects had been assessed annually with a number of cognitive instruments, including the Mini-Mental State Examination
Demographic and disease variables of controls vs. AD
Table 1 shows comparisons of demographic and disease variables between controls and AD. Age at death was significantly different between the groups, with controls being older than AD. However, the age ranges of the groups were similar (64–101 for control, 62–88 for AD), and while the oldest control subject was aged 101, the next oldest control was 88. Besides, age did not correlate with CB1 receptor immunoreactivity or [3H]SR141716A binding density in either the control or AD group (Spearman or
Discussion and conclusion
Using postmortem brain tissues from a cohort of well-characterized subjects with AD and aged controls, we did not find significant differences in the immunoreactivity of cannabinoid CB1 receptors in various areas of the forebrain and basal ganglia (Fig. 1A). Our immunoblotting data were corroborated with saturation binding assays using [3H]SR141716A in a subset of subjects. In a separate study, we also showed that CB1 receptor RNA levels were not significantly changed in temporal cortex (see
Conflicts of interest
The authors declare that there are no conflicts of interest.
Funding
This study is supported by a centre grant from the Singapore National Medical Research Council (NMRC/CG/NUHS/2010) to PTH Wong, CP Chen and MKP Lai, as well as a project grant (DCR/P04/2007) to MKP Lai by the Department of Clinical Research, Singapore General Hospital. GK Wilcock is partly funded by the NIHR Biomedical Research Centre Programme, Oxford.
References (45)
- et al.
Nicotinic receptor abnormalities in Alzheimer's disease
Biol. Psychiatry
(2001) - et al.
Genetic deletion of CB1 receptors improves non-associative learning
Behav. Brain Res.
(2005) - et al.
“Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician
J. Psychiatr. Res.
(1975) Pyramidal neurone modulation: a therapeutic target for Alzheimer's disease
Neurodegeneration
(1996)- et al.
Alzheimer's disease and vascular dementia in developing countries: prevalence, management, and risk factors
Lancet Neurol.
(2008) - et al.
Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells
Neuron
(2001) Analysis of radioligand binding experiments. A collection of computer programs for the IBM PC
J. Pharmacol. Methods
(1985)- et al.
SR141716A, a potent and selective antagonist of the brain cannabinoid receptor
FEBS Lett.
(1994) - et al.
Disrupted muscarinic M1 receptor signaling correlates with loss of protein kinase C activity and glutamatergic deficit in Alzheimer's disease
Neurobiol. Aging
(2007) - et al.
Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system
Neuroscience
(1998)
Cannabinoid receptor binding and messenger RNA expression in human brain: An in vitro receptor autoradiography and in situ hybridization histochemistry study of normal aged and Alzheimer's brains
Neuroscience
Memantine for dementia
Cochrane Database Syst. Rev.
Endocannabinoid system: emerging role from neurodevelopment to neurodegeneration
Mini Rev. Med. Chem.
Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer's disease brains
J. Neurosci.
Cholinesterase inhibitors for Alzheimer's disease
Cochrane Database Syst. Rev.
Neuropathological stageing of Alzheimer-related changes
Acta Neuropathol.
CB2 receptors in the brain: role in central immune function
Br. J. Pharmacol.
Alzheimer's disease; taking the edge off with cannabinoids?
Br. J. Pharmacol.
Alzheimer disease: diagnosis, costs, and dimensions of treatment
Alzheimer Dis. Assoc. Disord.
The marijuana component cannabidiol inhibits β-amyloid-induced tau protein hyperphosphorylation through Wnt/β-catenin pathway rescue in PC12 cells
J. Mol. Med.
A molecular link between the active component of marijuana and Alzheimer's disease pathology
Mol. Pharm.
Cited by (61)
An enquiry to the role of CB1 receptors in neurodegeneration
2023, Neurobiology of DiseaseWomen are taking the hit: Examining the unique consequences of cannabis use across the female lifespan
2023, Frontiers in NeuroendocrinologyThe endocannabinoid system and aging
2023, Neurobiology and Physiology of the Endocannabinoid SystemEndocannabinoid system alterations in Alzheimer's disease: A systematic review of human studies
2020, Brain ResearchCitation Excerpt :Studies including MCI patients used recognised MCI diagnostic criteria, but did not report MCI clinical subtypes (Fonteh et al. 2013, González-Domínguez et al. 2016). 12 studies reported 100% of AD cases had either clinically probable or definite diagnoses (Ahmad et al. 2014, Ahmad et al. 2016, Altamura et al. 2015, Benito et al. 2003, Farooqui et al. 1988, Fonteh et al. 2013, Grünblatt et al. 2007, Jung et al. 2012, Lee et al. 2010, Mulder et al. 2011, Solas et al. 2013, Westlake et al. 1994). Risk of selection bias was low with the majority of studies using recognised criteria for AD diagnosis and with adequately described recruitment procedures.
G protein-coupled receptors in neurodegenerative diseases
2019, GPCRs: Structure, Function, and Drug DiscoveryCannabinoid pharmacology/therapeutics in chronic degenerative disorders affecting the central nervous system
2018, Biochemical Pharmacology