JOURNAL OF NEUROCHEMISTRY | 2017 | 142 | 624–648 doi: 10.1111/jnc.14098 , , , *Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, USA †New York State Psychiatric Institute, New York City, New York, USA ‡Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York City, New York, USA §Department of Psychiatry, New York University Langone Medical Center, New York City, New York, USA Abstract enzymes that catabolize these compounds, has been shown Most neurodegenerative disorders (NDDs) are characterized to contribute to the development of NDDs in several animal by cognitive impairment and other neurological defects. The models and human studies. In this review, we discuss the definite cause of and pathways underlying the progression of functions of the endocannabinoid system in NDDs and these NDDs are not well-defined. Several mechanisms have converse the therapeutic efficacy of targeting the endo- been proposed to contribute to the development of NDDs. cannabinoid system to rescue NDDs. These mechanisms may proceed concurrently or succes- Keywords: Alzheimer’s disease, CB1 receptors, Huntington’s sively, and they differ among cell types at different develop- disease, Loss of neurons, motor and memory behavior, mental stages in distinct brain regions. The endocannabinoid Parkinson’s disease. system, which involves cannabinoid receptors type 1 (CB1R) J. Neurochem. (2017) 142, 624–648. and type 2 (CB2R), endogenous cannabinoids and the Cannabinoids are naturally occurring compounds found in the plant Cannabis sativa. Of over 500 different compounds Received April 6, 2017; revised manuscript received May 22, 2017; present in the plant, only approximately 85 are termed accepted June 2, 2017. cannabinoids (Brenneisen 2007). The most well-known Address for correspondence and reprint request to Dr Balapal S. among these compounds is delta-9-tetrahydrocannabinol Basavarajappa, Division of Analytical Psychopharmacology, Nathan (D9-THC) (Dewey 1986; Hollister 1986). D9-THC elicits Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd, Orangeburg, New York, NY 10962, USA. E-mail: basavaraj.balapal its psychoactive effects by binding to receptors on the cell @nki.rfmh.org membrane called cannabinoid receptors (CBRs) (Howlett Abbreviations used: 2-AG, 2-arachidonylglycerol; ABHD4, abhydro- et al. 1990). These receptors are present in both the central lase domain 4; AEA, arachidonylethanolamide (anandamide); AMPAR, nervous system (CNS) and the periphery and are classified as a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; AMT, type 1 (CB1R) and type 2 (CB2R). Signaling downstream of AEA membrane transporter; BDNF, brain-derived neurotrophic factor; fi CB1R, cannabinoid receptor type 1; CB2R, cannabinoid receptor type 2; these CBRs is signi cantly involved in a variety of standard DAGL, diacylglycerollipase; EC, endocannabinoid; FAAH, fatty acid functions as well as several pathophysiological functions of amide hydrolase; FAK, focal adhesion kinase; GABAA, gamma-amino the CNS. Signaling events of CB1R and CB2R are depicted butyric acid-A receptor; GDE1, glycerophosphodiesterase; GPCR, G in Figs 1 and 2 respectively. Discovery of the first endoge- protein coupled receptor; MAGL, monoacylglycerol lipase; MAPK, nous cannabinoid substance, anandamide (N-arachidonoyl mitogen-activated protein kinase; miRNAs, microRNAs; NAPE-PLD, N-acylphosphatidylethanolamine-specific phospholipase D; N-ArPE, ethanolamine, AEA) (Devane and Axelrod 1994), in the N-arachidonyl phosphatidylethanolamine; NAT, N-acyltransferase; NMDA, brain emphasized the importance of the cannabinoid receptor N-methyl-D-aspartate; PGH2, prostaglandin H2; PTPN22, phosphatase; and its endogenous ligands in the regulation of a wide variety VR1, vanilloid receptor type 1; D9-THC, delta-9-tetrahydrocannabinol. 624 © 2017 International Society for Neurochemistry, J. Neurochem. (2017) 142, 624--648 Mechanisms of NDs 625 of biological functions (Pertwee 1997). Later, 2-arachidonoyl (Ohno-Shosaku et al. 1998, 2000, 2001, 2002; Wilson and glycerol (2-AG) was identified as a second endogenous Nicoll 2001, 2002; Wilson et al. 2001). The discovery of cannabinoid (Sugiura et al. 2006). These two endogenous ECs such as AEA and 2-AG and the widespread localization cannabinoids are derivatives of arachidonic acid (Fig. 3) and of CB1Rs in the brain have stimulated considerable excite- are synthesized and metabolized by different pathways ment regarding the role of the EC system in Alzheimer’s (Fig. 4a and b). Both AEA and 2-AG act on the CBRs to disease (AD). AD is the most devastating neurodegenerative elicit their biological activities; therefore, they are termed disorder in humans, and the most common symptom of AD endocannabinoids (ECs). ECs are lipophilic in nature and are is difficulty in retaining and recalling recently learned synthesized on demand from membrane phospholipids, and information. Cognitive deficits of AD patients correlate with they can readily partition into and diffuse throughout cellular cerebral disturbances in sensitive brain areas, largely in the membranes without storage in vesicles. After their release frontal cortex and the hippocampal region, areas that are rich from the post-synaptic neuron, ECs bind to CB1Rs located in CB1Rs (Glass et al. 1997; Biegon and Kerman 2001). AD on the pre-synaptic membrane to inhibit neurotransmitter pathology is characterized by the accumulation of b-amyloid release (Ohno-Shosaku et al. 2001; Berghuis et al. 2007; (Ab), neurofibrillary tangles consisting of hypophosphory- Harkany et al. 2008). ECs are removed from the synaptic lated tau, the loss of particular subsets of neurons, and junction after CB1R activation by process of cellular neuroinflammation resulting from glial activation. Although transport followed by hydrolysis. Anandamide is hydrolyzed the existence of familial AD, which shows early onset, has in post-synaptic neurons by fatty acid amide hydrolase been characterized, this form only accounts for a small (FAAH), thus terminating its action (Varvel et al. 2006, proportion of cases (Hardy 1996a,b; Campion et al. 1999; 2007). After CB1R activation, 2-AG is hydrolyzed in pre- Hardy and Selkoe 2002). The real cause of sporadic AD is synaptic neurons by monoacylglycerol lipase (MAGL) [see unknown, but numerous risk factors have been identified, recent reviews (Basavarajappa 2015; Lu and Anderson including hypercholesterolemia, ischemic stroke, hyperten- 2017)] (Fig. 4a and b). This retrograde signaling provides a sion, the ApoE4 allele and diabetes (Grammas 2011; mechanism for inhibitory feedback to regulate neurotrans- Carnevale et al. 2016; Hamel et al. 2016). mitter release in the brain. This unique function of ECs has Limited numbers of studies have reported reduced densi- provided a strong rationale for investigating them as ties of CB1Rs in aged animals (Mailleux and Vanderhaeghen therapeutic targets for autoimmune disease, stroke and some 1992a; Romero et al. 1998). ECs were shown to decrease other severe neurodegenerative diseases, including Alzhei- significantly with age in the mouse hippocampus and frontal mer’s disease (AD), Huntington’s disease (HD) and Parkin- cortex (Maroof et al. 2014). An autoradiographic examina- son’s disease (PD). We have recently reviewed the functions tion of sections of normal post-mortem brain suggested a no of EC system in the normal brain (Basavarajappa 2015; Lu significant reduction in CB1R binding with age (Ahmad and Anderson 2017); therefore, the current study aims to et al. 2014). Several investigators have studied the changes present the new understanding of the role and involvement of associated with the EC system during the progression of AD the EC system in neurodegenerative disorders (Tables 1 disease. Correlation analyses based on post-mortem cortical and 2). brain tissues (Brodmann area 10) from a cohort of neu- ropathologically confirmed AD patients indicated lower EC system and AD CB1R levels than in age-matched controls (Solas et al. The distribution of CB1Rs in the rodent adult brain is highly 2013). These lower CB1R levels correlated with hypophagia heterogeneous, with the highest densities of receptors present but not with any AD molecular markers or cognitive status in the basal ganglia, including the substantia nigra pars (Solas et al. 2013). The levels of AEA were reduced in the reticulata (SNr) and the globus pallidus, in the hippocampus, hippocampus of a mouse genetic model of AD (transgenic particularly within the dentate gyrus, and in the molecular mice overexpressing amyloid precursor protein, APP) layer of the cerebellum. Low levels of CB1Rs are also found (TgAPP-2576) (Kofalvi et al. 2016). The ECs acting through in the brainstem (Howlett 2002). There is a similar distribu- transient receptor potential cation channel subfamily V tion of CB1Rs in humans (Glass et al. 1997; Biegon and member 1 (TRPV1) were suggested to play a significant Kerman 2001). The highest densities are found in limbic role in Ab-induced cognitive impairment in D3 receptor KO cortices, with much lower levels observed within primary mice (Micale et al. 2010). sensory and motor regions, pointing an important role in Cannabinoid receptor agonists such as AEA and noladin motivational (limbic) and cognitive (Association) informa- ether have been shown to provide protection against the Ab- tion processing. CB1Rs have been shown to be localized pre- peptide induced neurotoxicity in neurons differentiated