Alzheimer’s Disease: Neurotransmitters Involved and the Possible New Strategies

Alzheimer’s Disease (AD) is the progressive neurodegenerative disorder associated with many pathophysiological conditions. The aim of present review is to understand the learning and cognitive processes and study the various parameters related to Alzheimer’s Disease. The pathophysiological mechanism of the AD has been studied and neurotransmitters used in learning process and cognitive function have been described. The main pathophysiological symptom behind AD is β-Amyloid plaque and neurofibrillary entangles. The other reasons of AD include synaptic failure, decrease in calcium regulation, inflammatory mediators, problem in insulin signaling, depletion of neurotransmitters, oxidative stress and mitochondrial dysfunction. Cholinergic system is the major system involved in the learning and cognitive behaviour. The roles of various other neurotransmitters like angiotensin, GABA, dopamine, adrenaline, serotonin, histamine, nitric oxide and nerve growth factors have also been described. The neurotransmitters like acetylcholine, adrenaline and dopamine have been found to improve cognitive behaviour while NMDA, GABA, serotonin, histamine and angiotensin have diminishing effect on memory. © 2019 iGlobal Research and Publishing Foundation. All rights reserved. Cite this article as: Maratha, S.K.; Falls, N.; Vashist, N.; Yadav, S.; Gahlot, V. Alzheimer’s disease: neurotransmitters involved and the possible new strategies. Indo Global J. Pharm. Sci., 2019; 9(1): 512. DOI: http://doi.org/10.35652/IGJPS.2019.9102 . Indo Global Journal of Pharmaceutical Sciences, 2019; 9(1): 5-12 6 resulting in increased brain β-amyloid [3]. The discrimination of vascular dementia from AD is dependent on evidence of a cerebrovascular disorder. There are unusual less cases of pure vascular dementia without neurodegenerative changes. The autopsy of clinically diagnosed vascular dementia emphasized on the presence of pathological signs of AD. Mild cognitive impairment has been defined as the earliest forms of dementia that may partly convert into AD [4]. NEUROMODULATORS USED IN LEARNING PROCESS AND MEMORY Various Neurotransmitters, Neuromodulators and their associated receptor systems used in learning and memory processes are given below: 1. Role of Cholinergic System The decrease in cognitive ability is mostly related to a suppression of cholinergic neurotransmission. Nicotine and nicotinic agonists have been found to upgrade cognition in animals [5]. Increased contact with nicotine results in positive changes on central cholinergic neurotransmitters and memory function [6]. Acetylcholinesterase (AChE) is an enzyme that blocks the effects of acetylcholine at the neurohumoral junctions of cholinergic nerve endings [2]. Anticholinesterase agents that are capable of crossing the blood-brain barrier have shown efficacy in the treatment of AD. Biochemical investigation of the samples obtatined from the brains of AD suffering patients shows reduction in nicotinic acetylcholine receptors (nAChRs), a potentiation in butyrylcholinesterase, reduction in Ach and inactivating enzymes [7]. Butyrylcholinesterase and AChE help abolish Ach demonstrate by hydrolyzing the transmitter, thereby inactivating it. The most unguarded neurons in AD appears to be those showing increased levels of nAChRs, particularly those containing the α7 subunit [8], and the numbers of nAChRs in addition to few of their linked proteins change in AD [9]. Not only have α7 nAChRs been found be localized with plaques but α7 and α4 subunits are also positively corrected with neurons that accumulate amyloid β (A β) [10]. It is sure that AD involves damage to neurons of cholinergic nervous system in brain in addition to an overall decrease in nAChRs, and it appears that various subunits are differentially up or down-regulated in AD in different brain parts and various cell types. 2. Role of Dopaminergic System Dopamine, being the major catecholamine neurotransmitter in the mammalian brain, controls various functions, involving food intake, locomotor activity, emotion, cognition, and endocrine management. Cerebral levels of dopamine and its active metabolite homovanillic acid have been documented to be reduced in cortex and amygdala regions of patients diagnosed with AD. Dopamine (DA) receptor agonist, pergolide has been found to improve memory in human beings [11]. D2 dopamine receptor antagonist, (-)-sulpiride, showed antagonizing effect on the memory enhancing effect of caffeine [12]. 3. Role of Serotonergic System Role of various 5-HT receptors in the physiology of memory processes and their adjustment by the serotonin depletor pchlorophenylalanine (pCPA) has been shown in rats using shuttle box [13]. 5-HT2 antagonist, mianserin improved cognitive function in chronic schizophrenic patients [14]. 5HT 3 receptor antagonist, ondansetron improved learning and cognitive behaviour in animal models [15]. 5-HT reduces long term potentiation (LTP) in hippocampal portion by preventing the activation of NMDA receptors and the increase of AMPAmediated currents that leads to LTP induction [16]. The presynaptic 5-HT1A receptors decrease glutamate secretion [17]. 5-HT1B receptors are located on the axons terminals of Cauda Aquna 1 pyramidal neurons. The memory impairment was seen after a treatment with 5-HT1B agonists is may be the result of reduction in excitatory neurotransmission in circuits which are part of the hippocampus activity [18]. 4. Role of GABA-ergic System Muscimol, a GABAA receptor agonist was found to impair retrieval in rodents, when administered immediately after acquisition trial [19]. On the other hand, bicuculline is a GABAA-antagonist when injected 30 minutes prior to training, enhanced memory in chicks [20] and in rats [21]. Baclofen, a GABAB receptor agonist, impaired spatial learning in rats through activation of presynaptic GABAB receptors in a dose dependent manner [22]. Activation of GABAA and GABAB receptors may be involved in the processes leading to impairment of memory [23]. GABAA receptors negotiate fast-acting inhibitory actions in the brain and activation of GABAA receptor cause hyperpolarization and decreased activity of neurons. Compounds that enhance the action of GABA can impair memory processing, while the compounds that reduce the action of GABA can enhance memory processing, especially the possession process [24]. 5. Role of Histamine Histamine plays a crucial role as a neurotransmitter in the central nervous system and actively participates in various physiological functions across specific receptors including the H1, H2, H3 and H4 histamine receptors [5]. The H1, H2, and H3 subtypes are expressed in the CNS, and H4 subtype is only Indo Global Journal of Pharmaceutical Sciences, 2019; 9(1): 5-12 7 found in periphery, specifically in bone marrow and leukocytes [25]. It has been accepted that histamine with other transmitter systems involve in higher brain tasks such as memory and learning [26]. The earlier reports also showed that co-administration of sulpiride with histamine during repeated pre-treatment of histamine reversed the amnesia induced by post-training histamine [23]. Histamine and histidine improved short term-memory and reversed the spatial memory loss induced by MK-801, probably through postsynaptic H1-receptors [27]. Thioperamide, the first specific H3-receptor antagonist improved memory consolidation and reversed the cognitive dysfunction induced by scopolamine or dizocilpine [28]. An injection of clobenpropit (5, 10 ug per site, depending on dose) markedly improved the reference memory with emphasis on day to day memory effect initiated by MK-801, probably through increased release of endogenous histamine [27] 6. Role of NMDA (N-methyl-D-aspartate) Activation of NMDA receptor was reported to affect learning and cognitive behaviour [29] Memantine, a non-competitive NMDA receptor antagonist, marketed for treatment of AD [30]. Memantine has neuroprotective properties and can block β-amyloid induced neurodegeneration [31]. Glutamate activates a variety of postsynaptic receptors, including the Nmethyl-D-aspartate (NMDA) receptor, which has been specifically involved in memory procedure, dementia, and the pathophysiological progression of AD. Glutamate receptors when stimulated, produces Reactive Oxygen Species (ROS) and involvement of programmed cell-death series [32]. 7. Role of Angiotensin Converting Enzyme (ACE) The brain RAS plays a crucial role in the management of neurogenic hypertension [33], cerebrovascular fluid homeostasis [34] and sodium intake [35]. Latest studies show clinical and experimental proof has suggested that brain RAS has participated in strokes [36], in addition to other neurological diseases, such as AD [37], and Parkinson's disease [38], Angiotensin II regulates long term memory appearance but does not affect memory storage [39]. ACE inhibitors like captopril and enalapril have shown to improve cognition in different animal models of memory and learning [40] 8. Role of Nerve Growth Factor Nerve growth factor (NGF) is the most important parameter to defend cholinergic neurons from neurodegeneration [41]. Nerve Growth Factor (NGF), Brain-Derived Nerve Factor (BDNF), Glial-Derived Nerve Factor (GDNF) intricated in the result of neurodegenerative diseases. Different neurons will depend upon various growth factors to protect themselves from continuous damages, for example NGF protects cholinergic system neurons most probable injuries[42], where as for dopaminergic neuron, the effect is more efficiently maintained by BDNF [43]. 9. Role of Nitric Oxide Release of NO free radical in brain leads to neurodegeneration and hence may provoke memory impairment [44]. L-arginine, which is a nitric oxide donor, improved memory of rats [45]. Only three isoforms of nitric oxide synthase (NOS) have been discovered till date and they are named depending to the cell types from which they were first separated. They are designated as neuronal