Albert A. Davis

Bio: Albert A. Davis is an academic researcher from Emory University. The author has contributed to research in topics: Neurodegeneration & Muscarinic acetylcholine receptor. The author has an hindex of 11, co-authored 12 publications receiving 2337 citations.

Novel Selective Allosteric Activator of the M1 Muscarinic Acetylcholine Receptor Regulates Amyloid Processing and Produces Antipsychotic-Like Activity in Rats

Abstract: Recent studies suggest that subtype-selective activators of M(1)/M(4) muscarinic acetylcholine receptors (mAChRs) may offer a novel approach for the treatment of psychotic symptoms associated with schizophrenia and Alzheimer's disease. Previously developed muscarinic agonists have provided clinical data in support of this hypothesis, but failed in clinical development because of a lack of true subtype specificity and adverse effects associated with activation of other mAChR subtypes. We now report characterization of a novel highly selective agonist for the M(1) receptor with no agonist activity at any of the other mAChR subtypes, termed TBPB [1-(1'-2-methylbenzyl)-1,4'-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one]. Mutagenesis and molecular pharmacology studies revealed that TBPB activates M(1) through an allosteric site rather than the orthosteric acetylcholine binding site, which is likely critical for its unprecedented selectivity. Whole-cell patch-clamp recordings demonstrated that activation of M(1) by TBPB potentiates NMDA receptor currents in hippocampal pyramidal cells but does not alter excitatory or inhibitory synaptic transmission, responses thought to be mediated by M(2) and M(4). TBPB was efficacious in models predictive of antipsychotic-like activity in rats at doses that did not produce catalepsy or peripheral adverse effects of other mAChR agonists. Finally, TBPB had effects on the processing of the amyloid precursor protein toward the non-amyloidogenic pathway and decreased Abeta production in vitro. Together, these data suggest that selective activation of M(1) may provide a novel approach for the treatment of symptoms associated with schizophrenia and Alzheimer's disease.

A selective allosteric potentiator of the M1 muscarinic acetylcholine receptor increases activity of medial prefrontal cortical neurons and restores impairments in reversal learning.

Abstract: M 1 muscarinic acetylcholine receptors (mAChRs) may represent a viable target for treatment of disorders involving impaired cognitive function However, a major limitation to testing this hypothesis has been a lack of highly selective ligands for individual mAChR subtypes We now report the rigorous molecular characterization of a novel compound, benzylquinolone carboxylic acid (BQCA), which acts as a potent, highly selective positive allosteric modulator (PAM) of the rat M 1 receptor This compound does not directly activate the receptor, but acts at an allosteric site to increase functional responses to orthosteric agonists Radioligand binding studies revealed that BQCA increases M 1 receptor affinity for acetylcholine We found that activation of the M 1 receptor by BQCA induces a robust inward current and increases spontaneous EPSCs in medial prefrontal cortex (mPFC) pyramidal cells, effects which are absent in acute slices from M 1 receptor knock-out mice Furthermore, to determine the effect of BQCA on intact and functioning brain circuits, multiple single-unit recordings were obtained from the mPFC of rats that showed BQCA increases firing of mPFC pyramidal cells in vivo BQCA also restored discrimination reversal learning in a transgenic mouse model of Alzheimer9s disease and was found to regulate non-amyloidogenic APP processing in vitro , suggesting that M 1 receptor PAMs have the potential to provide both symptomatic and disease modifying effects in Alzheimer9s disease patients Together, these studies provide compelling evidence that M 1 receptor activation induces a dramatic excitation of PFC neurons and suggest that selectively activating the M 1 mAChR subtype may ameliorate impairments in cognitive function

Wlds mice are resistant to paclitaxel (taxol) neuropathy

Abstract: The WldS mouse is a unique mutant strain that demonstrates the remarkable phenotype of prolonged survival of transected axons ("slow Wallerian degeneration"). In these studies, we tested whether this neuroprotective phenotype extends to axonal degeneration seen in a progressive peripheral neuropathy. WldS and wild-type mice were intoxicated with the cancer chemotherapeutic agent paclitaxel (Taxol). The severity of the resultant sensory neuropathy was compared with behavioral, physiological, and pathological measures. WldS mice were resistant to paclitaxel neuropathy by all measures, and the resistance was because of protection against axonal degeneration. These studies demonstrate for the first time that the WldS mouse is more than a slow Wallerian degeneration phenotype, emphasizing the mechanistic link between Wallerian degeneration and peripheral neuropathy. Understanding how this mutant gene confers protection against axonal degeneration will provide important clues toward prevention of axonal degeneration in several human neurological disorders.

A Subpopulation of Neuronal M4 Muscarinic Acetylcholine Receptors Plays a Critical Role in Modulating Dopamine-Dependent Behaviors

Abstract: Acetylcholine (ACh) regulates many key functions of the CNS by activating cell surface receptors referred to as muscarinic ACh receptors (M 1 –M 5 mAChRs). Like other mAChR subtypes, the M 4 mAChR is widely expressed in different regions of the forebrain. Interestingly, M 4 mAChRs are coexpressed with D 1 dopamine receptors in a specific subset of striatal projection neurons. To investigate the physiological relevance of this M 4 mAChR subpopulation in modulating dopamine-dependent behaviors, we used Cre/loxP technology to generate mutant mice that lack M 4 mAChRs only in D 1 dopamine receptor-expressing cells. The newly generated mutant mice displayed several striking behavioral phenotypes, including enhanced hyperlocomotor activity and increased behavioral sensitization following treatment with psychostimulants. These behavioral changes were accompanied by a lack of muscarinic inhibition of D 1 dopamine receptor-mediated cAMP stimulation in the striatum and an increase in dopamine efflux in the nucleus accumbens. These novel findings demonstrate that a distinct subpopulation of neuronal M 4 mAChRs plays a critical role in modulating several important dopamine-dependent behaviors. Since enhanced central dopaminergic neurotransmission is a hallmark of several severe disorders of the CNS, including schizophrenia and drug addiction, our findings have substantial clinical relevance.

Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders

Abstract: Despite G-protein-coupled receptors (GPCRs) being among the most fruitful targets for marketed drugs, intense discovery efforts for several GPCR subtypes have failed to deliver selective drug candidates. Historically, drug discovery programmes for GPCR ligands have been dominated by efforts to develop agonists and antagonists that act at orthosteric sites for endogenous ligands. However, in recent years, there have been tremendous advances in the discovery of novel ligands for GPCRs that act at allosteric sites to regulate receptor function. These compounds provide high selectivity, novel modes of efficacy and may lead to novel therapeutic agents for the treatment of multiple psychiatric and neurological human disorders.

The changing scene of amyotrophic lateral sclerosis

Abstract: Several recent breakthroughs have provided notable insights into the pathogenesis of amyotrophic lateral sclerosis (ALS), with some even shifting our thinking about this neurodegenerative disease and raising the question as to whether this disorder is a proteinopathy, a ribonucleopathy or both. In addition, these breakthroughs have revealed mechanistic links between ALS and frontotemporal dementia, as well as between ALS and other neurodegenerative diseases, such as the cerebellar atrophies, myotonic dystrophy and inclusion body myositis. Here, we summarize the new findings in ALS research, discuss what they have taught us about this disease and examine issues that are still outstanding.

Alzheimer's disease: Targeting the Cholinergic System

Abstract: Acetylcholine (ACh) has a crucial role in the peripheral and central nervous systems. The enzyme choline acetyltransferase (ChAT) is responsible for synthesizing ACh from acetyl-CoA and choline in the cytoplasm and the vesicular acetylcholine transporter (VAChT) uptakes the neurotransmitter into synaptic vesicles. Following depolarization, ACh undergoes exocytosis reaching the synaptic cleft, where it can bind its receptors, including muscarinic and nicotinic receptors. ACh present at the synaptic cleft is promptly hydrolyzed by the enzyme acetylcholinesterase (AChE), forming acetate and choline, which is recycled into the presynaptic nerve terminal by the high-affinity choline transporter (CHT1). Cholinergic neurons located in the basal forebrain, including the neurons that form the nucleus basalis of Meynert, are severely lost in Alzheimer's disease (AD). AD is the most ordinary cause of dementia affecting 25 million people worldwide. The hallmarks of the disease are the accumulation of neurofibrillary tangles and amyloid plaques. However, there is no real correlation between levels of cortical plaques and AD-related cognitive impairment. Nevertheless, synaptic loss is the principal correlate of disease progression and loss of cholinergic neurons contributes to memory and attention deficits. Thus, drugs that act on the cholinergic system represent a promising option to treat AD patients.