Cholinesterase Inhibitors Used for the Management of Alzheimer’s Disease: A Review

Alzheimer’s disease (AD) is defined as a progressive neurodegenerative disorder that has lately become the top reason for dementia in the elderly population (usually above 60-65 years). As mentioned before, most AD cases are sporadic and have a late onset. This disease is characterized by impairment of higher cognitive functions like deficits in memory, language comprehension, coordination, etc. The primary pathophysiology behind Alzheimer’s disease is loss of cholinergic innervation due to the formation of neuritic (senile) amyloid-beta plaques and tau protein-containing neurofibrillary tangles (NFTs) in parts of the brain associated with memory functions. These neurofibrillary tangles (NFTs) and amyloid β plaques can cause the induction of other aetiologies of Alzhedisease-likes like neuroinflammation and central hyperexcitability. The brain's main regions affected by Alzheimer’s disease are the neocortex, the basal nucleus of Meynert, and the hippocampus. These areas are associated with higher cognitive functions like memory, arousal, attention, sensory processing, etc. Thus, cholinesterase inhibitors have been widely used as first-line drug therapy for symptomatic relief in Alzheimer’s disease. They function by inhibiting acetylcholinesterase or catabolizing it and henceforth enhancing synaptic availability of Acetylcholine. The commonly prescribed drugs of this class include donepezil, galantamine, physostigmine, metrifonate, and rivastigmine. This article will discuss the widely used cholinesterase inhibitors (old & new) for managing AD symptoms in detail.

Sudomotor dysfunction in patients with gluten neuropathy

Background and aim Gluten neuropathy (GN) is a common neurological manifestation of gluten sensitivity (GS), characterized by serological evidence of GS, while other risk factors for developing neuropathy are absent. The degree of small fiber dysfunction in GN has not been studied in depth to date. Small fiber involvement may lead to pain, thermal perception abnormalities, and sweat gland dysfunction. Sudomotor innervation refers to the cholinergic innervation of the sympathetic nervous system through small fibers in the sweat glands. The aim of our study was to assess the sudomotor function of GN patients. Methods Patients with GN were recruited. Clinical and neurophysiological data were obtained. HLA-DQ genotyping was performed. The skin electrochemical conductance (ESC) was measured with SUDOSCANTM. Results Thirty-two patients (25 males, mean age 69.5±10.2 years) were recruited. Thirteen patients (40.6%) had abnormal sudomotor function of the hands. Sixteen patients (50%) had abnormal sudomotor function of the feet. Twenty-one patients (65.6%) had abnormal sudomotor function of either the hands or feet. Sudomotor dysfunction did not correlate with the type of neuropathy (length-dependent neuropathy or sensory ganglionopathy), gluten-free diet adherence, severity of neuropathy, and duration of disease or HLA-DQ genotype. No differences in the ESC were found between patients with painful and patients with painless GN. Conclusion Sudomotor dysfunction affects two-thirds of patients with GN. The lack of correlation between pain and sudomotor dysfunction suggests different patterns of small fiber involvement in patients with GN.

Aortic Butyrylcholinesterase is Reduced in Spontaneously Hypertensive Rats

Despite the fact that vessels have sparse cholinergic innervation, acetylcholine (ACh), the primary neurotransmitter of parasympathetic nervous system, has been commonly used in physiological experiments to assess vascular function. ACh is hydrolyzed by two cholinesterases (ChE), namely acetylcholin-esterase and butyrylcholinesterase (BChE). However, little is known about these enzymes in blood vessels. The aim of the project was to characterize the expression and activity of ChE in rat aorta. As the effect of ACh on vascular tone depends on the presence of endothelium, Wistar rats were used as a model with intact endothelium and spontaneously hypertensive rats as a model of impaired endothelial function. Relative expressions of both ChE in different parts of the aorta were determined using RT-qPCR. Enzyme activities were assessed in tissue homogenates by Ellman's assay. Here we showed that both ChE are present in each part of rat aorta, while mRNA is more abundant for BChE than for AChE, irrespective of aortic compartment or genotype. Normotensive Wistar rats possess higher aortic mRNA expression and activity of BChE compared to SHR. We concluded that BChE is the dominant type of ChE in rat aorta and it might play an important role in the regulation of vascular tone

Evaluation of sweating responses in patients with collagen disease using the quantitative sudomotor axon reflex test (QSART): a study protocol for an investigator-initiated, prospective, observational clinical study

IntroductionSweat secretion is controlled by the sympathetic nervous system and is less active during winter than in the summer. Raynaud’s phenomenon is affected by an excessive strain of the sympathetic nerves after exposure to a cold environment, thus reducing the quality of life of patients with collagen disease. Herein, we focus on the eccrine sweat glands that receive both adrenergic and cholinergic innervation. Our hypothesis is that excessive activation of sympathetic nerve in Raynaud’s phenomenon can affect sweating, especially in winter. This study is designed to evaluate the neuroactive sweating responses in patients with collagen disease and to assess its association with skin findings in peripheral circulatory disorders.Methods and analysisThe study will be conducted at a single centre in Japan. Patients with systemic sclerosis, Sjogren’s syndrome, systemic lupus erythematosus, mixed connective tissue disease, and dermatomyositis will be assessed using the quantitative sudomotor axon reflex test. The primary outcomes will be sweat volume and reaction time due to axon reflex and the Raynaud’s condition score. The secondary outcomes will include patient background, skin symptoms (digital ulcers, pernio-like eruptions, subcutaneous calcifications, telangiectasia, nailfold capillary dilatation/bleeding and degree of skin sclerosis) and skin surface temperature. Evaluation will be done two times, during the summer and winter, allowing for the assessment of seasonal differences in sweating responses.Ethics and disseminationEthical approval of this study was certified by the clinical research review board of Nagasaki University Hospital (Reference number: CRB19-001). We will disseminate the findings of this study through peer-reviewed publications and conference presentations.Trial registration numberjRCTs072190009; pre-results.

Peripheral Nerve Impairment in a Mouse Model of Alzheimer’s Disease

Sarcopenia, a geriatric syndrome involving loss of muscle mass and strength, is often associated with the early phases of Alzheimer’s disease (AD). Pathological hallmarks of AD including amyloid β (Aβ) aggregates which can be found in peripheral tissues such as skeletal muscle. However, not much is currently known about their possible involvement in sarcopenia. We investigated neuronal innervation in skeletal muscle of Tg2576 mice, a genetic model for Aβ accumulation. We examined cholinergic innervation of skeletal muscle in adult Tg2576 and wild type mice by immunofluorescence labeling of tibialis anterior (TA) muscle sections using antibodies raised against neurofilament light chain (NFL) and acetylcholine (ACh) synthesizing enzyme choline acetyltransferase (ChAT). Combining this histological approach with real time quantification of mRNA levels of nicotinic acetylcholine receptors, we demonstrated that in the TA of Tg2576 mice, neuronal innervation is significantly reduced and synaptic area is smaller and displays less ChAT content when compared to wild type mice. Our study provides the first evidence of reduced cholinergic innervation of skeletal muscle in a mouse model of Aβ accumulation. This evidence sustains the possibility that sarcopenia in AD originates from Aβ-mediated cholinergic loss.

Altered Cortical Cholinergic Network in Parkinson’s Disease at Different Stage: A Resting-State fMRI Study

The cholinergic system is critical in Parkinson’s disease (PD) pathology, which accounts for various clinical symptoms in PD patients. The substantia innominata (SI) provides the main source of cortical cholinergic innervation. Previous studies revealed cholinergic-related dysfunction in PD pathology at early stage. Since PD is a progressive disorder, alterations of cholinergic system function along with the PD progression have yet to be elucidated. Seventy-nine PD patients, including thirty-five early-stage PD patients (PD-E) and forty-four middle-to-late stage PD patients (PD-M), and sixty-four healthy controls (HC) underwent brain magnetic resonance imaging and clinical assessments. We employed seed-based resting-state functional connectivity analysis to explore the cholinergic-related functional alterations. Correlation analysis was used to investigate the relationship between altered functional connectivity and the severity of motor symptoms in PD patients. Results showed that both PD-E and PD-M groups exhibited decreased functional connectivity between left SI and left frontal inferior opercularis areas and increased functional connectivity between left SI and left cingulum middle area as well as right primary motor and sensory areas when comparing with HC. At advanced stages of PD, functional connectivity in the right primary motor and sensory areas was further increased. These altered functional connectivity were also significantly correlated with the Unified Parkinson’s Disease Rating Scale motor scores. In conclusion, this study illustrated that altered cholinergic function plays an important role in the motor disruptions in PD patients both in early stage as well as during the progression of the disease.

Blockade of TRPC Channels Limits Cholinergic-Driven Hyperexcitability and Seizure Susceptibility After Traumatic Brain Injury

We investigated the contribution of excitatory transient receptor potential canonical (TRPC) cation channels to posttraumatic hyperexcitability in the brain 7 days following controlled cortical impact model of traumatic brain injury (TBI) to the parietal cortex in male adult mice. We investigated if TRPC1/TRPC4/TRPC5 channel expression is upregulated in excitatory neurons after TBI in contribution to epileptogenic hyperexcitability in key hippocampal and cortical circuits that have substantial cholinergic innervation. This was tested by measuring TRPC1/TRPC4/TRPC5 protein and messenger RNA (mRNA) expression, assays of cholinergic function, neuronal Ca2+ imaging in brain slices, and seizure susceptibility after TBI. We found region-specific increases in expression of TRPC1, TRPC4, and TRPC5 subunits in the hippocampus and cortex following TBI. The dentate gyrus, CA3 region, and cortex all exhibited robust upregulation of TRPC4 mRNA and protein. TBI increased cFos activity in dentate gyrus granule cells (DGGCs) and layer 5 pyramidal neurons both at the time of TBI and 7 days post-TBI. DGGCs displayed greater magnitude and duration of acetylcholine-induced rises in intracellular Ca2+ in brain slices from mice subjected to TBI. The TBI mice also exhibited greater seizure susceptibility in response to pentylenetetrazol-induced kindling. Blockade of TRPC4/TRPC5 channels with M084 reduced neuronal hyperexcitation and impeded epileptogenic progression of kindling. We observed that the time-dependent upregulation of TRPC4/TRPC5-containing channels alters cholinergic responses and activity of principal neurons acting to increase proexcitatory sensitivity. The underlying mechanism includes acutely decreased acetylcholinesterase function, resulting in greater Gq/11-coupled muscarinic receptor activation of TRPC channels. Overall, our evidence suggests that TBI-induced plasticity of TRPC channels strongly contributes to overt hyperexcitability and primes the hippocampus and cortex for seizures.

Arg1+ microglia are critical for shaping cognition in female mice

Diversity within microglia, the resident brain immune cells, is reported. Whether microglial subsets constitute different subtypes with intrinsic properties and unique functions has not been fully elucidated. Here, we describe a microglial subtype characterized by the expression of the enzyme Arginase-1, i.e. Arg1+microglia, which is found predominantly in the cholinergic neuron-rich forebrain region during early postnatal development. Arg1+ microglia are frequently observed in close apposition to neurons and exhibit a distinct molecular signature including upregulation of genes such as Apoe, Clec7a, Igf1, Lgals3 and Mgl2. Arg1-knockout in microglia results in a deficient cholinergic innervation along with impaired dendritic spine maturation in the hippocampus where cholinergic neurons project, impaired long-term potentiation and cognitive behavioural deficiencies in female mice. Our results expand on microglia diversity and provide insights into distinctive spatiotemporal functions exerted by microglial subtypes.

Where Dopaminergic and Cholinergic Systems Interact: A Gateway for Tuning Neurodegenerative Disorders

Historically, many investigations into neurodegenerative diseases have focused on alterations in specific neuronal populations such as, for example, the loss of midbrain dopaminergic neurons in Parkinson’s disease (PD) and loss of cholinergic transmission in Alzheimer’s disease (AD). However, it has become increasingly clear that mammalian brain activities, from executive and motor functioning to memory and emotional responses, are strictly regulated by the integrity of multiple interdependent neuronal circuits. Among subcortical structures, the dopaminergic nigrostriatal and mesolimbic pathways as well as cholinergic innervation from basal forebrain and brainstem, play pivotal roles in orchestrating cognitive and non-cognitive symptoms in PD and AD. Understanding the functional interactions of these circuits and the consequent neurological changes that occur during degeneration provides new opportunities to understand the fundamental inter-workings of the human brain as well as develop new potential treatments for patients with dysfunctional neuronal circuits. Here, excerpted from a session of the European Behavioral Pharmacology Society meeting (Braga, Portugal, August 2019), we provide an update on our recent work in behavioral and cellular neuroscience that primarily focuses on interactions between cholinergic and dopaminergic systems in PD models, as well as stress in AD. These brief discussions include descriptions of (1) striatal cholinergic interneurons (CINs) and PD, (2) dopaminergic and cholinergic modulation of impulse control, and (3) the use of an implantable cell-based system for drug delivery directly the into brain and (4) the mechanisms through which day life stress, a risk factor for AD, damage protein and RNA homeostasis leading to AD neuronal malfunction.

Multiple Sources of Cholinergic Input to the Superior Olivary Complex

The superior olivary complex (SOC) is a major computation center in the brainstem auditory system. Despite previous reports of high expression levels of cholinergic receptors in the SOC, few studies have addressed the functional role of acetylcholine in the region. The source of the cholinergic innervation is unknown for all but one of the nuclei of the SOC, limiting our understanding of cholinergic modulation. The medial nucleus of the trapezoid body, a key inhibitory link in monaural and binaural circuits, receives cholinergic input from other SOC nuclei and also from the pontomesencephalic tegmentum. Here, we investigate whether these same regions are sources of cholinergic input to other SOC nuclei. We also investigate whether individual cholinergic cells can send collateral projections bilaterally (i.e., into both SOCs), as has been shown at other levels of the subcortical auditory system. We injected retrograde tract tracers into the SOC in gerbils, then identified retrogradely-labeled cells that were also immunolabeled for choline acetyltransferase, a marker for cholinergic cells. We found that both the SOC and the pontomesencephalic tegmentum (PMT) send cholinergic projections into the SOC, and these projections appear to innervate all major SOC nuclei. We also observed a small cholinergic projection into the SOC from the lateral paragigantocellular nucleus of the reticular formation. These various sources likely serve different functions; e.g., the PMT has been associated with things such as arousal and sensory gating whereas the SOC may provide feedback more closely tuned to specific auditory stimuli. Further, individual cholinergic neurons in each of these regions can send branching projections into both SOCs. Such projections present an opportunity for cholinergic modulation to be coordinated across the auditory brainstem.