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Authors: Froestl, Wolfgang | Muhs, Andreas | Pfeifer, Andrea

Article Type: Review Article

Abstract: Scientists working in the field of Alzheimer's disease and, in particular, cognitive enhancers are very productive. The review on Drugs interacting with Enzymes was accepted in August 2012. However, this field is very dynamic. New potential targets for the treatment of Alzheimer's disease were identified. This update describes drugs interacting with 60 enzymes versus 43 enzymes in the first paper. Some compounds progressed in their development, while many others were discontinued. The present review covers the evolution of research in this field through April 2014.

Keywords: Alzheimer's disease, cognitive enhancers, donepezil, enzymes, galantamine, memory, rivastigmine

DOI: 10.3233/JAD-140402

Citation: Journal of Alzheimer's Disease, vol. 42, no. 1, pp. 1-68, 2014

Authors: Froestl, Wolfgang | Muhs, Andreas | Pfeifer, Andrea

Article Type: Review Article

Abstract: Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer's disease, schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing, applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To classify the compounds, a concept is proposed assigning drugs to 19 categories according to their mechanism(s) of action, …in particular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, antioxidants, metal chelators, and disease modifying drugs meaning small molecules, vaccines, and monoclonal antibodies interacting with amyloid-β and tau. For drugs whose mechanism of action is not known, they are either classified according to structure, e.g., peptides, or their origin, e.g., natural products. This review covers the evolution of research in this field over the last 25 years. Show more

Keywords: Alzheimer's disease, cognitive enhancers, donepezil, enzymes, galantamine, memory, rivastigmine

DOI: 10.3233/JAD-2012-121537

Citation: Journal of Alzheimer's Disease, vol. 33, no. 3, pp. 547-658, 2013

Authors: Froestl, Wolfgang | Muhs, Andreas | Pfeifer, Andrea

Article Type: Review Article

Abstract: Scientists working in the fields of Alzheimer's disease and, in particular, cognitive enhancers are very productive. The review “Cognitive enhancers (nootropics): drugs interacting with receptors” was accepted for publication in July 2012. Since then, new targets for the potential treatment of Alzheimer's disease were identified. This update describes drugs interacting with 42 receptors versus 32 receptors in the first paper. Some compounds progressed in their development, while many others were discontinued. The present review covers the evolution of research in this field through March 2014.

Keywords: Alzheimer's disease, cognitive enhancers, memantine, memory, nootropics, receptors

DOI: 10.3233/JAD-140228

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 961-1019, 2014

Authors: Froestl, Wolfgang | Muhs, Andreas | Pfeifer, Andrea

Article Type: Review Article

Abstract: Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer's disease, schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing, applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To classify the compounds, a concept is proposed assigning drugs to 18 categories according to their mechanism(s) of action, …in particular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, antioxidants, metal chelators, and disease-modifying drugs meaning small molecules, vaccines, and monoclonal antibodies interacting with amyloid-β and tau. For drugs, whose mechanism of action is not known, they are either classified according to structure, e.g., peptides, or their origin, e.g., natural products. The review covers the evolution of research in this field over the last 25 years. Show more

Keywords: Alzheimer's disease, cognitive enhancers, memantine, memory, nootropics, receptors

DOI: 10.3233/JAD-2012-121186

Citation: Journal of Alzheimer's Disease, vol. 32, no. 4, pp. 793-887, 2012

Authors: Froestl, Wolfgang | Pfeifer, Andrea | Muhs, Andreas

Article Type: Review Article

Abstract: Scientists working in the field of Alzheimer's disease and, in particular, cognitive enhancers, are very productive. The review “Drugs interacting with Targets other than Receptors or Enzymes. Disease-modifying Drugs” was accepted in October 2012. In the last 20 months, new targets for the potential treatment of Alzheimer's disease were identified. Enormous progress was realized in the pharmacological characterization of natural products with cognitive enhancing properties. This review covers the evolution of research in this field through May 2014.

Keywords: Amyloid-β aggregation inhibitors, antibodies, antioxidants, cognitive enhancers, metal chelators, natural products, nootropics, peptides, psychostimulants, stem cells, tau, vaccines

DOI: 10.3233/JAD-141206

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1079-1149, 2014

Authors: Froestl, Wolfgang | Pfeifer, Andrea | Muhs, Andreas

Article Type: Review Article

Abstract: Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer's disease, schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing, applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To classify the compounds, a concept is proposed assigning drugs to 19 categories according to their mechanism(s) of action, …in particular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, antioxidants, metal chelators, and disease modifying drugs, meaning small molecules, vaccines, and monoclonal antibodies interacting with amyloid-β and tau. For drugs, whose mechanism of action is not known, they are either classified according to structure, e.g., peptides, or their origin, e.g., natural products. The review covers the evolution of research in this field over the last 25 years. Show more

Keywords: Amyloid-β aggregation inhibitors, antibodies, antioxidants, cognitive enhancers, metal chelators, natural products, peptides, psychostimulants, tau, vaccines

DOI: 10.3233/JAD-121729

Citation: Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 1-114, 2013

Authors: Theunis, Clara | Adolfsson, Oskar | Crespo-Biel, Natalia | Piorkowska, Kasia | Pihlgren, Maria | Hickman, David T. | Gafner, Valérie | Borghgraef, Peter | Devijver, Herman | Pfeifer, Andrea | Van Leuven, Fred | Muhs, Andreas

Article Type: Research Article

Abstract: The microtubule-associated protein Tau is an intrinsically unfolded, very soluble neuronal protein. Under still unknown circumstances, Tau protein forms soluble oligomers and insoluble aggregates that are closely linked to the cause and progression of various brain pathologies, including Alzheimer’s disease. Previously we reported the development of liposome-based vaccines and their efficacy and safety in preclinical mouse models for tauopathy. Here we report the use of a liposomal vaccine for the generation of a monoclonal antibody with particular characteristics that makes it a valuable tool for fundamental studies as well as a candidate antibody for diagnostic and therapeutic applications. The specificity …and affinity of antibody ACI-5400 were characterized by a panel of methods: (i) measuring the selectivity for a specific phospho-Tau epitope known to be associated with tauopathy, (ii) performing a combination of peptide and protein binding assays, (iii) staining of brain sections from mouse preclinical tauopathy models and from human subjects representing six different tauopathies, and (iv) evaluating the selective binding to pathological epitopes on extracts from tauopathy brains in non-denaturing sandwich assays. We conclude that the ACI-5400 antibody binds to protein Tau phosphorylated at S396 and favors a conformation that is typically present in the brain of tauopathy patients, including Alzheimer’s disease. Show more

Keywords: Antibody binding sites, Alzheimer’s disease, monoclonal antibody, protein conformation, tauopathies

DOI: 10.3233/JAD-160695

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 585-599, 2017

Authors: Paganetti, Paolo | Antoniello, Katia | Devraj, Kavi | Toni, Nicolas | Kieran, Dairin | Madani, Rime | Pihlgren, Maria | Adolfsson, Oskar | Froestl, Wolfgang | Schrattenholz, André | Liebner, Stefan | Havas, Daniel | Windisch, Manfred | Cirrito, John R. | Pfeifer, Andrea | Muhs, Andreas

Article Type: Research Article

Abstract: The formation and accumulation of toxic amyloid-β peptides (Aβ) in the brain may drive the pathogenesis of Alzheimer's disease. Accordingly, disease-modifying therapies for Alzheimer's disease and related disorders could result from treatments regulating Aβ homeostasis. Examples are the inhibition of production, misfolding, and accumulation of Aβ or the enhancement of its clearance. Here we show that oral treatment with ACI-91 (Pirenzepine) dose-dependently reduced brain Aβ burden in AβPPPS1, hAβPPSL , and AβPP/PS1 transgenic mice. A possible mechanism of action of ACI-91 may occur through selective inhibition of muscarinic acetylcholine receptors (AChR) on endothelial cells of brain microvessels and enhanced Aβ …peptide clearance across the blood-brain barrier. One month treatment with ACI-91 increased the clearance of intrathecally-injected Aβ in plaque-bearing mice. ACI-91 also accelerated the clearance of brain-injected Aβ in blood and peripheral tissues by favoring its urinal excretion. A single oral dose of ACI-91 reduced the half-life of interstitial Aβ peptide in pre-plaque mhAβPP/PS1d mice. By extending our studies to an in vitro model, we showed that muscarinic AChR inhibition by ACI-91 and Darifenacin augmented the capacity of differentiated endothelial monolayers for active transport of Aβ peptide. Finally, ACI-91 was found to consistently affect, in vitro and in vivo, the expression of endothelial cell genes involved in Aβ transport across the Blood Brain Barrier (BBB). Thus increased Aβ clearance through the BBB may contribute to reduced Aβ burden and associated phenotypes. Inhibition of muscarinic AChR restricted to the periphery may present a therapeutic advantage as it avoids adverse central cholinergic effects. Show more

Keywords: Aβ brain efflux, Aβ clearance, Aβ homeostasis, AβPP transgenic mice, amyloid-β peptides, drug treatment, muscarinic receptors, plaque deposition

DOI: 10.3233/JAD-131091

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 767-786, 2014