The utility of muscarinic agonists in the treatment of Alzheimer's disease

Alzheimer’s disease is a progressive neurological disorder characterized by amyloid plaques and neurofibrillary tangles along with memory and cognitive deficits associated with a loss of basal forebrain cholinergic neurons. Efforts to treat Alzheimer’s disease have focused on compounds that elevate cholinergic activity such as cholinesterase inhibitors and direct acting muscarinic and nicotinic agonists. Low efficacy and poor selectivity of available compounds have limited the clinical utility of muscarinic agonists. Recent studies suggesting a role for muscarinic agonists in regulating the production of Aβ raise the possibility that selective M₁ agonists could be useful in treating not only the symptoms, but also the underlying cause(s) of Alzheimer’s disease. Thus, renewed efforts have focused on the development of compounds with improved selectivity for M₁ receptors and lower toxicity. 5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine (CDD-0102) is a potent M₁ agonist with a low side effect profile that enhances memory function in animal models of Alzheimer’s disease. The available preclinical data suggest that CDD-0102 may be useful in the treatment of Alzheimer’s disease.     

Nicotinic receptor modulation: advantages for successful Alzheimer's disease therapy

Galantamine is a modest acetylcholinesterase inhibitor (AChEI) that is also an allosteric potentiating ligand (APL) of nicotinic acetylcholine receptors (nAChRs). In this report, these two effects are shown to be dependent upon each other using a realistic computer model of the cholinergic synaptic cleft. The model is based upon realistic estimates of the anatomy of a neuronal synapse, the kinetic states of pre- and postsynaptic nAChRs, and the acetylcholinesterase enzyme. The number of open postsynaptic nAChRs per action potential is a measure of cholinergic neurotransmission. Using mathematical equations and published data, the effect of the AChEI and APL actions of galantamine is quantitatively described and compared to the effects of pure AChEIs. The model shows that galantamine--compared to similar concentrations of pure AChEIs--is able to compensate for its somewhat modest effect on the cholinesterase enzyme with its allosteric modulatory effects that include the additional benefit of a lower degree of receptor desensitization.     

No response to high-dose muscarinic agonist therapy in Alzheimer's disease

Cholinergic deficiency is the most consistent transmitter system abnormality in Alzheimer's disease. To test the acute therapeutic efficacy of cholinergic replacement, seven patients with presenile onset of Alzheimer's type dementia received maximum tolerated doses (10 mg/d) of the selective muscarinic agonist, RS-86, in combination with a peripherally active anticholinergic glycopyrrolate (6 mg/d), in a double-blind placebo-controlled design. No consistent, clinically significant cognitive improvement could be discerned in these mild to moderately demented patients, despite attainment of central RS-86 levels approximating those that affect behavior in the experimental animal. Muscarinic agonist monotherapy may thus be inadequate to benefit Alzheimer's type dementia.     

M1 muscarinic agonists target major hallmarks of Alzheimer's disease--an update

The M1 muscarinic receptor (M1 mAChR), preserved in Alzheimer's disease (AD), is a pivotal target that links major hallmarks of AD, e.g. cholinergic deficiency, cognitive dysfunctions, beta-amyloid (Abeta) and tau pathologies. Some muscarinic agonists, while effective in AD, had limited clinical value due to adverse effects and lack of M1 selectivity. The M1 selective muscarinic agonists AF102B [Cevimeline], AF150(S) and AF267B - i) elevated alphaAPPs, decreased Abeta levels and tau hyperphosphorylation, and blocked Abeta-induced neurotoxicity, in vitro, via M1 mAChR-modulation of kinases (e.g. PKC, MAPK and GSK3beta); ii) restored cognitive deficits, cholinergic markers, and decreased tau hyperphosphorylation in relevant models with a wide safety margin. AF267B decreased brain Abeta levels in hypercholesterolemic rabbits and decreased CSF Abeta42 in rabbits and removed vascular Abeta42 deposition from cortex in cholinotoxin-treated rabbits. In 3x transgenic-AD mice that recapitulate the major pathologies and cognitive deficits of AD, chronic AF267B treatment rescued cognitive deficits and decreased Abeta42 and tau pathologies in the cortex and hippocampus (not amygdala), via M1 mAChR-activation of ADAM17/TACE and decreased BACE1 steady state levels and inhibition of GSK3beta, extending findings from above. CONCLUSIONS: A comprehensive therapy should target all AD hallmarks, regardless of the culprit(s) responsible for the disease. In this context, AF267B is the 1(st) reported low MW CNS-penetrable mono-therapy that meets this challenge. Clinical trials will determine if AF267B may become an important therapy in AD.     

GABA-agonist therapy for Alzheimer's disease

Evidence suggesting a reduction of cerebral gamma-aminobutyric acid (GABA) neurons in Alzheimer's disease has been reported. To evaluate the possible contribution of GABA system dysfunction to the intellectual decline associated with this disorder, a controlled therapeutic trial of a potent and specific GABA agonist, THIP [4,5,6,7-tetrahydroisoxazolo(5,4,-c)pyridin-3-ol], was undertaken. Six Alzheimer patients with mild to moderately severe dementia and low spinal-fluid GABA levels received THIP at maximum individually tolerated dosage. No significant change in cognitive function could be discerned, despite attainment of dose levels that produced centrally mediated adverse effects similar to those of other GABA agonists. The results support the views that pharmacologic attempts to stimulate central GABA-mediated synaptic function may not confer therapeutic benefit to patients with Alzheimer's disease and that a GABA system deficit may not serve as a critical determinant of the dementia that characterizes this disorder.     

AF150(S) and AF267B: M1 muscarinic agonists as innovative therapies for Alzheimer's disease

The M1 muscarinic agonists AF102B (Cevimeline, EVOXACTM: prescribed in USA and Japan for Sjogren's Syndrome), AF150(S) and AF267B--1) are neurotrophic and synergistic with neurotrophins such as nerve growth factor and epidermal growth factor; 2) elevate the non-amyloidogenic amyloid precursor protein (alpha-APPs) in vitro and decrease beta-amyloid (A beta) levels in vitro and in vivo; and 3) inhibit A beta- and oxidative-stress-induced cell death and apoptosis in PC12 cells transfected with the M1 muscarinic receptor. These effects can be combined with the beneficial effects of these compounds on some other major hallmarks of Alzheimer's disease (AD) (e.g. tau hyperphosphorylation and paired helical filaments [PHF]; and loss of cholinergic function conducive to cognitive impairments.) These drugs restored cognitive impairments in several animal models for AD, mimicking different aspects of AD, with a high safety margin (e.g. AF150[S] >1500 and AF267B >4500). Notably, these compounds show a high bioavailability and a remarkable preference for the brain vs. plasma following p.o. administration. In mice with small hippocampi, unlike rivastigmine and nicotine, AF150(S) and AF267B restored cognitive impairments also on escape latency in a Morris water maze paradigm in reversal learning. Furthermore, in aged and cognitively impaired microcebes (a natural animal model that mimics AD pathology and cognitive impairments), prolonged treatment with AF150(S) restored cognitive and behavioral impairments and decreased tau hyperphosphorylation, PHF and astrogliosis. Our M1 agonists, alone or in polypharmacy, may present a unique therapy in AD due to their beneficial effects on major hallmarks of AD.     

Stem cell therapy for Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder which impairs the memory and intellectual abilities of the affected individuals. Loss of episodic as well as semantic memory is an early and principal feature. The basal forebrain cholinergic system is the population of neurons most affected by the neurodegenerative process. Extracellular as well as intracellular deposition of beta-amyloid or Abeta (Abeta) protein, intracellular formation of neurofibrillary tangles and neuronal loss are the neuropathological hallmarks of AD. In the last few years, hopes were raised that cell replacement therapy would provide cure by compensating the lost neuronal systems. Stem cells obtained from embryonic as well as adult tissue and grafted into the intact brain of mice or rats were mostly followed by their incorporation into the host parenchyma and differentiation into functional neural lineages. In the lesioned brain, stem cells exhibited targeted migration towards the damaged regions of the brain, where they engrafted, proliferated and matured into functional neurones. Neural precursor cells can be intravenously administered and yet migrate into brain damaged areas and induce functional recovery. Observations in animal models of AD have provided evidence that transplanted stem cells or neural precursor cells (NPCs) survive, migrate, and differentiate into cholinergic neurons, astrocytes, and oligodendrocytes with amelioration of the learning/memory deficits. Besides replacement of lost or damaged cells, stem cells stimulate endogenous neural precursors, enhance structural neuroplasticity, and down regulate proinflammatory cytokines and neuronal apoptotic death. Stem cells could also be genetically modified to express growth factors into the brain. In the last years, evidence indicated that the adult brain of mammals preserves the capacity to generate new neurons from neural stem/progenitor cells. Inefficient adult neurogenesis may contribute to the pathogenesis of AD and other neurodegenerative disorders. An attempt at mobilizing this endogenous pool of resident stem-like cells provides another attractive approach for the treatment of AD. Studies in patients with AD indicated decreased hippocampal volume derived by neurodegeneration. Intriguingly, many drugs including antidepressants, lithium, acetyl cholinesterase inhibitors, and ginkgo biloba, were able to enhance the impaired neurogenesis in this disease process. This paved the way towards exploring the possible pharmacological manipulation of neurogenesis which would offer an alternative approach for the treatment of AD.     

Abeta vaccine therapy for Alzheimer's disease]

In 1999, Schenk et al reported that vaccination of PDAPP-transgenic mice with synthetic Abeta42 in complete Freund's adjuvant showed markedly decrease of the amyloid burden in the brain. The second trial of vaccine, AN1792, for Alzheimer's patients was halted because of meningoencephalitis found in 6% of patients and one autopsy case was reported. Here, we comment the methods and the immunological mechanisms of Abeta vaccine therapy and discuss the pathological changes in the brain and side effects after AN1792 treatment. Furthermore, we present an oral Abeta vaccine therapy for Alzheimer's disease with the recombinant adeno-associated virus (AAV) vector that we developed.     

Immunization therapy in Alzheimer's disease

Alzheimer's disease (AD) is a common and devastating neurodegenerative disease. The incidence of AD is increasing in Western societies. The current treatment of AD is mostly symptomatic and ineffective in stopping or reversing the cognitive impairment. One of the exciting and effective new treatments developed in experimental AD is immunization against amyloid-beta peptide. This article provides an overview of immunization therapy in AD and examines the future prospects of this therapeutic modality.     

Statin therapy in Alzheimer's disease

Previous studies have suggested that statin therapy may be of benefit in treating Alzheimer's disease (AD). We initiated a double-blind, placebo-controlled, randomized (1:1) trial with a 1-year exposure to once-daily atorvastatin calcium (80 mg; two 40 mg tablets) or placebo among individuals with mild-to-moderate AD [Mini-Mental State Examination (MMSE) score of 12–28]. Stable dose use of cholinesterase inhibitors, estrogen and vitamin E was allowed, as was the use of most other medications in the treatment of co-morbidities. We demonstrated that atorvastatin treatment produced significantly ( P  = 0.003) improved performance on cognition and memory after 6 months of treatment (ADAS-cog) among patients with mild-to-moderate AD. This superior effect persisted at 1 year ( P  = 0.055). This positive effect on the ADAS-cog performance after 6 months of treatment was more prominent among individuals entering the trial with higher MMSE scores ( P  = 0.054). Benefit on other clinical measures was identified in the atorvastatin-treated population compared with placebo. Accordingly, atorvastatin therapy may be of benefit in the treatment of mild-to-moderately affected AD patients, but the level of benefit produced may be predicated on earlier treatment. Evidence also suggests that atorvastatin may slow the progression of mild-to-moderate AD, thereby prolonging the quality of an afflicted individual's life.     

Association analysis for the muscarinic M1 receptor genetic polymorphisms and Alzheimer's disease

In the ongoing search to reveal the pathophysiology of Alzheimer's disease (AD), the cholinergic system is important due to its role in cognitive function and its significance with respect to the results of postmortem pathology and animal model studies. For this investigation, we tested the hypothesis that the allelic variant (C267A) of the cholinergic receptor muscarinic 1 (CHRM1) confers susceptibility to AD or is related to its age of onset, in a sample population of 232 AD patients and 169 normal controls. The distribution of the CHRM1 genotypes (p = 0.919) and alleles (p = 0.327) did not differ significantly comparing AD patients and controls, even after stratification according to apolipoprotein E genotype. The onset age was not significantly different comparing the CHRM1 genotype groups. Our negative findings suggest that it is unlikely that the CHRM1 C267A polymorphism plays a substantial role in conferring susceptibility to AD. We propose that other genetic variations of CHRM1, relating either to AD or to the therapeutic response for AD, may need further investigation.     

Self-maintenance therapy in Alzheimer's disease

A short-term residential treatment programme designed to prepare patients with dementia and caregivers for life with a progressive disease was evaluated in a one group pretest–posttest design. The multicomponent programme included: (1) intensive rehabilitation for patients, based on the concept of Self-Maintenance Therapy, and (2) an intervention programme for caregivers. The results showed a consistent improvement in patients' depression and in other psychopathological symptoms, which can be seen as directly beneficial for patients. Following treatment, caregivers also felt less depressed, less mentally fatigued and restless, and more relaxed. Controlled studies are needed to support the preliminary results presented and to address hypotheses about factors responsible for benefits as well as for treatment resistance. The concept of Self-Maintenance Therapy allowed the prediction that experiences that are in accordance with patients' self-structures and processes support patients' well-being, reduce psychopathological symptoms, and facilitate social participation.     

The peroxisome proliferators activated receptor-gamma agonists as therapeutics for the treatment of Alzheimer's disease and mild-to-moderate Alzheimer's disease: a meta-analysis

Alzheimer's disease (AD) is a devastating neurodegenerative disease and there is no effective therapy for it. Peroxisome proliferators activated receptor-gamma (PPAR-γ) agonists is a promising therapeutic approach for AD and has been widely studied recently, but no consensus was available up to now. To clarify this point, a meta-analysis was performed. We searched MEDLINE, EMBASE, Cochrane Central database, PUBMED, Springer Link database, SDOS database, CBM, CNKI and Wan fang database by December 2014. Standardized mean difference (SMD), relative risk (RR) and 95% confidence interval (CI) were calculated to assess the strength of the novel therapeutics for AD and mild-to-moderate AD. A total of nine studies comprising 1314 patients and 1311 controls were included in the final meta-analysis. We found the effect of PPAR-γ agonists on Alzheimer's Disease Assessment Scale – Cognitive Subscale (ADAS-cog) scores by using STATA software. There was no evidence for obvious publication bias in the overall meta-analysis. There is insufficient evidence of statistically incognition of AD and mild-to-moderate AD patients have been improved who were treated with PPAR-γ agonists in our research. However, PPAR-γ agonists may be a promising therapeutic approach in future, especially pioglitazone, with large-scale randomized controlled trials to confirm.     

Perspectives of therapy of Alzheimer's disease

Alzheimer's disease is the most common cause of memory disruption in elderly people. The main pathogenic factor of the disease is beta-amyloid protein, which may cause toxic damage of neurones. Other suggested pathogenic factors include an inflammatory process around the senile plaques, apoptosis and necrotic death of neurones, and, in consequence, changes in functioning of neurotransmitter systems. In this article the authors present the main directions in pharmacotherapy of Alzheimer's disease: causal therapy, which prevents the neurodegenerative changes and slows down the pathogenetic process, and symptomatic therapy. The aim of symptomatic therapy is to reduce memory disruption and psychiatric symptoms associated with the disease. Positive influence on cognitive processes is exerted by cholinergic drugs, e.g. the actually used inhibitors of acetylcholinesterase (rivastigmine, donepezil), the nootropic agents (piracetam, nefiracetam) and extracts of Gingko biloba. For treatment of the disease accompanying psychiatric symptoms (anxiety, depression, hallucinations, sleepness) the drugs with minimal influence on cognitive processes are recommended. Attempts at causal therapy are focussed on searching for the substances that can prevent the formation and toxicity of beta-amyloid (droloksifen, estrogens, agonists of muscarinic receptors M1), the cytotoxic influence of excitatory aminoacids (memantine, lamotrigine), calcium (nimodipine) and free radicals (selegiline, alpha-tocoferol), and the development of inflammatory process (non-steroidal antiinflammatory drugs). The new target of research is correction of deficits of nerve growth factor and neurotransmitters by intracerebral implantation of modified fibroblasts. Another way is prevention of the formation of amyloid plaques using appropriate antisense oligonucleotides.     

Functional neuroanatomy of successful paired associate learning in Alzheimer's disease

OBJECTIVE: The purpose of the study was to develop a strategy for functional imaging of neurodegenerative disorders that overcomes confounds associated with differential performance between patient and comparison groups. METHOD: Functional magnetic resonance imaging was used to examine responses to increasing difficulty of visuospatial paired associate learning in 12 patients with mild probable Alzheimer's disease and 12 age-matched healthy comparison subjects. Performance was matched across groups by only examining successful encoding and retrieval attempts. Adjustment for task difficulty was made on an individual basis so that the patients with Alzheimer's disease and the comparison subjects performed at the same relative levels of difficulty. RESULTS: A network of lateral and medial frontoparietal and occipital regions was engaged in all subjects during successful associative learning. As task difficulty increased, blood-oxygen-level-dependent responses increased linearly in occipitoparietal regions during encoding and retrieval. Differential activations in patients with Alzheimer's disease and comparison subjects were small and were found only when an uncorrected statistical threshold was used. CONCLUSIONS: By controlling for confounds of varying task difficulty and subsequent performance, remarkably similar brain activations were identified during successful paired associate learning in patients with Alzheimer's disease and in healthy comparison subjects. The study methods provide a useful model for further applications of functional imaging involving cognitive activation paradigms in the study of neuropsychiatric disorders.