Alzheimer Disease: Fisher A

Caccamo A, Fisher A, LaFerla FM. · Department of Neurobiology, University of California, Irvine, Irvine, CA 92697, USA. · Curr Alzheimer Res. · Pubmed #19355845 No free full text.

Abstract: Cholinergic deficit is a cardinal feature of Alzheimer's disease, and cholinesterase inhibitors represent one of the most prominent means of mitigating this dysfunction. Cholinesterase inhibitors provide mild symptomatic relief, although they lose their efficacy over time most likely because they are not disease-modifying agents. An alternative strategy for restoring cholinergic function and attenuating the cognitive decline involves acting on the receptors on which acetylcholine acts. Stimulation of muscarinic acetylcholine receptors and in particular the M1 subtype has been shown to have a beneficial effect in restoring cognition in patients with Alzheimer's disease and in attenuating Abeta and tau pathology in different animal models. In this review, we discuss the role of M1 agonists as a potential disease-modifying therapy for Alzheimer's disease.

Fisher A. · Israel Institute for Biological Research, PO Box 19, Ness-Ziona, Israel. · Neurotherapeutics. · Pubmed #18625455 No free full text.

Abstract: The only prescribed drugs for treatment of Alzheimer's disease (AD) are acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, and tacrine) and memantine, an NMDA antagonist. These drugs ameliorate mainly the symptoms of AD, such as cognitive impairments, rather than halting or preventing the causal neuropathology. There is currently no cure for AD and there is no way to stop its progression, yet there are numerous therapeutic approaches directed against various pathological hallmarks of AD that are extensively being pursued. In this context, the three major hallmark characteristics of AD (i.e., the CNS cholinergic hypofunction, formation of beta-amyloid plaques, and tangles containing hyperphosphorylated tau proteins) are apparently linked. Such linkages may have therapeutic implications, and this review is an attempt to analyze these versus the advantages and drawbacks of some cholinergic compounds, such as acetylcholinesterase inhibitors, M1 muscarinic agonists, M2 antagonists, and nicotinic agonists. Among the reviewed treatments, M1 selective agonists emerge, in particular, as potential disease modifiers.

Fisher A. · Israel Institute for Biological Research, Ness-Ziona, Israel. · Neurodegener Dis. · Pubmed #18322400 No free full text.

Abstract: The M1 muscarinic receptor (M1 mAChR) is a therapeutic target in Alzheimer's disease (AD) and the M1-selective muscarinic agonists AF102B, AF150(S) and AF267B are cognitive enhancers and potential disease modifiers. Notably, AF267B decreased cerebrospinal fluid beta-amyloid (Abeta(40) and Abeta(42)) in rabbits, decreased brain Abeta levels in hypercholesterolemic rabbits and vascular Abeta(42) deposition from the cortex in cholinotoxin-treated rabbits. In triple transgenic AD mice, AF267B reduced cognitive deficits and decreased Abeta(42) and tau pathologies in the cortex and hippocampus (not amygdala), via M1 mAChR activation of protein kinase C and a disintegrin and metalloproteinase domain 17 (ADAM17 or TACE) and decreased beta-site amyloid precursor protein-cleaving enzyme 1 and glycogen synthase kinase 3beta, respectively. AF267B is the first reported low-molecular-weight therapy that targets the major AD hallmarks.

Fisher A. · Israel Institute for Biological Research, P.O.Box 19, 74100 Ness-Ziona, Israel. · Curr Alzheimer Res. · Pubmed #18220527 No free full text.

Abstract: 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.

Bons N, Rieger F, Prudhomme D, Fisher A, Krause KH. · Institut BioPARK, Domaine de Chosal, Archamps, INSERM U 488, Hôpital du Kremlin-Bicêtre, Paris, France. · Genes Brain Behav. · Pubmed #16507003 No free full text.

Abstract: Age-associated dementia, in particular Alzheimer's disease (AD), will be a major concern of the 21st century. Research into normal brain aging and AD will therefore become increasingly important. As for other areas of medicine, the availability of good animal models will be a limiting factor for progress. Given the complexity of the human brain, the identification of appropriate primate models will be essential to further knowledge of the disease. In this review, we describe the features of brain aging and age-associated neurodegeneration in a small lemurian primate, the Microcebus murinus, also referred to as the mouse lemur. The mouse lemur has a relatively short life expectancy, and animals over 5 years of age are considered to be elderly. Among elderly mouse lemurs, the majority show normal brain aging, whereas approximately 20% develop neurodegeneration. This Microcebus age-associated neurodegeneration is characterized by a massive brain atrophy, abundant amyloid plaques, a cytoskeletal Tau pathology and a loss of cholinergic neurons. While elderly mouse lemurs with normal brain aging maintain memory function and social interaction, animals with age-associated neurodegeneration lose their cognitive and social capacities and demonstrate certain similarities with age-associated human AD. We conclude that M. murinus is an interesting primate model for the study of normal brain aging and the biochemical dysfunctions occurring in age-associated neurodegeneration. Mouse lemurs might also become an increasingly important model for the development of novel treatments in this domain.

Fisher A, Pittel Z, Haring R, Bar-Ner N, Kliger-Spatz M, Natan N, Egozi I, Sonego H, Marcovitch I, Brandeis R. · Israel Institute for Biological Research, 74100 Ness-Ziona, Israel. · J Mol Neurosci. · Pubmed #14501019 No free full text.

Abstract: M1 muscarinic receptors (M1 mAChRs) play a role in an apparent linkage of three major hallmarks of Alzheimer's disease (AD): beta-amyloid (Abeta) peptide; tau hyperphosphorylation and paired helical filaments (PHFs); and loss of cholinergic function conducive to cognitive impairments. We evaluated the M1 muscarinic agonists AF102B (Cevimeline, EVOXAC trade mark : prescribed for Sjøgren's syndrome), AF150(S), and AF267B on some of these hallmarks of AD. Activation of M1 mAChRs with these agonists leads, inter alia, to enhanced secretion of amyloid precursor protein (alpha-APP), (via alpha-secretase activation), to decreased Abeta (via gamma-secretase inhibition), and to inhibition of Abeta- and/or oxidative stress-induced cell death. In several animal models mimicking different aspects of AD, these drugs restored cognitive impairments, and in select cases induced a decrease in brain Abeta elevation, with a high safety margin, following po administration. Notably, 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. Studies from other labs showed that AF102B and talsaclidine (another M1 agonist) decreased cerbrospinal fluid (CSF) Abeta in AD patients following chronic treatment, being the first reported drugs with such a profile. The clinical significance of these studies remains to be elucidated, yet based on in vivo (rabbits) and in vitro studies (cell cultures), our M1 agonists can decrease brain Abeta, owing to a novel and dual complementary effect (e.g., inhibition of gamma-secretase and activation of alpha-secretase). Remarkably, although M1 agonists can decrease CSF Abeta in AD patients, an increased AD-type pathology in Parkinson's disease was recently been associated with chronic antimuscarinic treatment. In another aspect, these agonists decreased tau hyperphosphorylation in vitro and in vivo. Notably, nicotinic agonists or cholinesterase inhibitors increased tau hyperphosphorylation. In summary, the M1 agonists tested are effective on cognition and behavior and show unique disease-modifying properties owing to beneficial effects on major hallmarks of AD. This may place such drugs in the first line of modern AD therapies (e.g., beta- or gamma-secretase inhibitors, vaccines against Abeta, statins, and inhibitors of tau hyperphosphorylation).

Fisher A, Brandeis R, Haring R, Bar-Ner N, Kliger-Spatz M, Natan N, Sonego H, Marcovitch I, Pittel Z. · Israel Institute for Biological Research, Ness-Ziona, Israel. · J Neural Transm Suppl. · Pubmed #12456063 No free full text.

Abstract: The M1 muscarinic agonists AF102B, AF150(S) & AF267B--i) restored cognitive impairments in several animal models for AD with an excellent safety margin; ii) elevated alpha-APPs levels; iii) attenuated vicious cycles induced by A beta, and inhibited A beta- and oxidative stress-induced apoptosis; and iv) decreased tau hyperphosphorylation. AF150(S) and AF267B were more effectve than rivastigmine and nicotine in restoring memory impairments in mice with small hippocampi. In apolipoprotein E-knockout mice, AF150(S) restored cognitive impairments and cholinergic hypofunction and decreased tau hyperphosphorylation. In aged microcebes, AF150(S) restored cognitive and behavioral impairments and decreased tau hyperphosphorylation, paired helical filaments and astrogliosis. In rabbits, AF267B & AF150(S) decreased CSF A beta(1-42 & 1-40), while AF102B reduced A beta(1-40). Finally AF102B decreased CSF A beta(total) in AD patients. Taken together, M1 agonists may represent a unique therapy in AD due to their beneficial effects on three major hallmarks of AD--cholinergic hypofunction, A beta and tau protein hyperphosphorylation.

Fisher A. · Israel Institute for Biological Research, Ness-Ziona. · Jpn J Pharmacol. · Pubmed #11128032 links to  free full text

Abstract: The cholinergic hypofunction in Alzheimer's disease (AD) appears to be linked with two other major hallmarks of this disease, beta-amyloid and hyperphosphorylated tau protein. Formation of beta-amyloids might impair the coupling of M1 muscarinic acetylcholine receptors (mAChR) with G-proteins. This can lead to decreased signal transduction, a decrease of trophic and non-amyloidogenic amyloid precursor protein (APPs) and generation of more beta-amyloids, aggravating further the cholinergic deficiency. This review is an attempt to explore the M1 mAChR regulation of beta-amyloid metabolism, tau hyperphosphorylation and cognitive functions. The therapeutic potential of M1-selective muscarinic agonists including AF102B, AF150(S), AF267B (the AF series) is evaluated and compared, when possible, with several FDA-approved acetylcholinesterase inhibitors. These M1 agonists can elevate APPs, decrease tau protein phosphorylation/hyperphosphorylation in vitro and in vivo and restore cognitive impairments in several animal models for AD. Except for the M1 agonists, no other compounds were reported yet with combined effects; e.g., amelioration of cognition dysfunction and beneficial modulation of APPs/beta-amyloid together with tau hyperphosphorylation/phosphorylation. This property of M1 agonists to alter different aspects associated with AD pathogenesis could represent the most remarkable clinical value of such drugs.

Caccamo A, Oddo S, Billings LM, Green KN, Martinez-Coria H, Fisher A, LaFerla FM. · Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697, USA. · Neuron. · Pubmed #16504943 No free full text.

Abstract: We investigated the therapeutic efficacy of the selective M1 muscarinic agonist AF267B in the 3xTg-AD model of Alzheimer disease. AF267B administration rescued the cognitive deficits in a spatial task but not contextual fear conditioning. The effect of AF267B on cognition predicted the neuropathological outcome, as both the Abeta and tau pathologies were reduced in the hippocampus and cortex, but not in the amygdala. The mechanism underlying the effect on the Abeta pathology was caused by the selective activation of ADAM17, thereby shifting APP processing toward the nonamyloidogenic pathway, whereas the reduction in tau pathology is mediated by decreased GSK3beta activity. We further demonstrate that administration of dicyclomine, an M1 antagonist, exacerbates the Abeta and tau pathologies. In conclusion, AF267B represents a peripherally administered low molecular weight compound to attenuate the major hallmarks of AD and to reverse deficits in cognition. Therefore, selective M1 agonists may be efficacious for the treatment of AD.

Fisher A, Brandeis R, Bar-Ner RH, Kliger-Spatz M, Natan N, Sonego H, Marcovitch I, Pittel Z. · Israel Institute for Biological Research, Ness-Ziona. · J Mol Neurosci. · Pubmed #12212772 No free full text.

Abstract: 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.

Beach TG, Walker DG, Potter PE, Sue LI, Fisher A. · Sun Health Research Institute, 10515 Santa Fe Drive, Sun City, AZ 85372, USA. · Brain Res. · Pubmed #11423097 No free full text.

Abstract: Overproduction of the peptide amyloid beta (A beta) is a critical event in Alzheimer's disease (AD). Systemic administration of 3 M1-selective muscarinic agonists, AF102B, AF150S and AF267B, decreased cerebrospinal fluid (CSF) A beta concentrations; levels of CSF secreted beta-APP were not significantly altered. Rabbits treated for 5 days with s.c. injections of each drug (2 mg/kg/day) had levels of CSF A beta which were between 55 and 71% of control for A beta 1-40 and between 59 and 84% of control for A beta 1--42.

Fisher A, Michaelson DM, Brandeis R, Haring R, Chapman S, Pittel Z. · Israel Institute for Biological Research, P.O. Box 19, Ness-Ziona 74100, Israel. · Ann N Y Acad Sci. · Pubmed #11193170 No free full text.

Abstract: A cholinergic hypofunction in Alzheimer's disease (AD) may lead to formation of beta-amyloids that might impair the coupling of M1 muscarinic ACh receptors (mAChRs) with G proteins. This disruption in coupling can lead to decreased signal transduction, to a reduction in levels of trophic amyloid precursor proteins (APPs), and to generation of more beta-amyloids that can also suppress ACh synthesis and release, aggravating further the cholinergic deficiency. These "vicious cycles," a presynaptic and a postsynaptic one, may be inhibited, in principle, by M1 selective agonists. Such properties can be detected in the functionally selective M1 agonists from the AF series [e.g., project drugs, AF102B, AF150(S)]. These M1 agonists promote the nonamyloidogenic APP processing pathways and decrease tau protein phosphorylation. The effects on tau proteins suggest a link between M1 mAChR-mediated signal transduction system(s) and the neuronal cytoskeleton via regulation of phosphorylation of tau microtubule-associated protein. This may indicate a dual role for M1 agonists: as inhibitors of two "vicious cycles," one induced by beta-amyloids, and the other due to overactivation of certain kinases (e.g., glycogen synthase kinase-3, GSK-3) or downregulation of phosphatases, respectively. Prolonged administration of AF150(S) in apolipoprotein E-knockout mice restored cognitive impairments, cholinergic hypofunction, and tau hyperphosphorylation, and unveiled a high-affinity binding site to M1 mAChRs. Except M1 agonists, there are no reports of compounds having such combined effects, for example, amelioration of cognition dysfunction and beneficial modulation of APPs together with tau phosphorylation. This unique property of M1 agonists to alter different aspects of AD pathogenesis could represent the most remarkable, yet unexplored, clinical value of such compounds.

Fitten LJ, Ortiz F, Siembieda DW, O'Neill J, Halgren E, Fisher A. · U.S. Department of Veterans Affairs Sepulveda Medical Centers, Los Angeles, California, USA. · J Neuropsychiatry Clin Neurosci. · Pubmed #9990560 links to  free full text

Abstract: The cholinesterase inhibitor tacrine (THA) and the M1 muscarinic agonist AF102B (cevimeline), both reported to enhance cognition in animals and humans, were tested in 5 macaques for reduction of spontaneous, random movements. Monkeys were videotaped 1 hour after administration of normal saline vehicle, after low- and high-dose intramuscular AF102B, and after low- and high-dose oral THA. Two independent blind judges counted numbers of spontaneous movements made by each monkey over 12 consecutive 15-second segments for each drug condition. Both THA and AF102B reduced movement significantly at high doses without overt side effects, warranting further research on the agitation-reducing potential of cognition-enhancing cholinomimetic drugs.

Hanin I, Windisch M, Poewe W, Fisher A. · No affiliation provided · Neurodegener Dis. · Pubmed #18322365 No free full text.

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