Differential effects of allosteric M(1) muscarinic acetylcholine receptor agonists on receptor activation, arrestin 3 recruitment, and receptor downregulation.

Muscarinic acetylcholine receptors (mAChRs) are drug targets for multiple neurodegenerative and neuropsychiatric disorders, but the full therapeutic potential of mAChR-targeted drugs has not been realized, mainly because of a lack of subtype-selective agonists. Recent advances have allowed the development of highly selective agonists that bind to an allosteric site on the M(1) mAChR that is spatially distinct from the orthosteric acetylcholine binding site, but less is known about the profile of intracellular signals activated by orthosteric versus allosteric M(1) mAChR agonists. We investigated the activation and regulatory mechanisms of two structurally distinct allosteric M(1) mAChR agonists, AC260584 and TBPB.

Days to criterion as an indicator of toxicity associated with human Alzheimer amyloid-beta oligomers.

Objective: Recent evidence suggests that high molecular weight soluble oligomeric Abeta (oAbeta) assemblies (also known as Abeta-derived diffusible ligands, or ADDLs) may represent a primary neurotoxic basis for cognitive failure in Alzheimer disease (AD). To date, most in vivo studies of oAbeta/ADDLs have involved injection of assemblies purified from the cerebrospinal fluid of human subjects with AD or from the conditioned media of Abeta-secreting cells into experimental animals. We sought to study the bioactivities of endogenously formed oAbeta/ADDLs generated in situ from the physiological processing of human amyloid precursor protein (APP) and presenitin1 (PS1) transgenes.

Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm.

We performed a genome-wide association study on 1,292 individuals with abdominal aortic aneurysms (AAAs) and 30,503 controls from Iceland and The Netherlands, with a follow-up of top markers in up to 3,267 individuals with AAAs and 7,451 controls. The A allele of rs7025486 on 9q33 was found to associate with AAA, with an odds ratio (OR) of 1.21 and P = 4.

White Matter Integrity and Episodic Memory Performance in Mild Cognitive Impairment: A Diffusion Tensor Imaging Study.

White matter (WM) integrity in the medial temporal lobes and episodic memory performance was examined in patients with mild cognitive impairment (MCI) and age-matched cognitively intact controls. Material specific associations between WM in the left versus right hemisphere and verbal versus visual memory performance were examined as well. Fourteen right-handed amnestic MCI patients underwent diffusion tensor imaging (DTI) and received verbal (words, story) and visual (designs) memory tests.

Synthesis and In Vitro Evaluation of Imidazo[1,2-b]pyridazines as Ligands for β-Amyloid Plaques.

A series of imidazo[1,2-b]pyridazine derivatives were synthesized and evaluated for binding to amyloid plaques in vitro using synthetic aggregates of Aβ1-40. Binding affinities of these compounds were found to range from 11.0 to >1000 nM, depending on the various substitution patterns in the 6-position and 2-position.

Deletion of M1 muscarinic acetylcholine receptors increases amyloid pathology in vitro and in vivo.

Alzheimer's disease (AD) is a progressive neurological disorder that causes dementia and poses a major public health crisis as the population ages. Aberrant processing of the amyloid precursor protein (APP) is strongly implicated as a proximal event in AD pathophysiology, but the neurochemical signals that regulate APP processing in the brain are not completely understood. Activation of muscarinic acetylcholine receptors (mAChRs) has been shown to affect APP processing and AD pathology, but less is known about the roles of specific mAChR subtypes.

A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors.

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.

Multiplex SILAC analysis of a cellular TDP-43 proteinopathy model reveals protein inclusions associated with SUMOylation and diverse polyubiquitin chains.

Transactive response (TAR) DNA-binding protein 43 (TDP-43) is a major protein component within ubiquitin-positive inclusions of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Although TDP-43 is a nuclear DNA/RNA-binding protein, in pathological conditions, TDP-43 has been reported to redistribute to the cytoplasm where it is cleaved and forms insoluble, ubiquitinated, and phosphorylated inclusions. Here we present a cellular model in which full-length human TDP-43 or a splicing isoform (TDP-S6) that lacks the C terminus is overexpressed in a human cell line and mouse primary neurons.

Mild cognitive impairment in Parkinson's disease: subtypes and motor characteristics.

The aims of this project were to determine the risk factors for and clinical characteristics of mild cognitive impairment (MCI) in Parkinson's disease (PD). We performed a retrospective record review of 72 non-demented PD patients (age: 57.79 +/- 10.

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

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.

The impact of vascular comorbidities on qualitative error analysis of executive impairment in Alzheimer's disease.

Recent evidence suggests that patients with Alzheimer's disease (AD) and vascular comorbidities (VC) perform worse across measures of verbal reasoning and abstraction when compared to patients with AD alone. We performed a qualitative error analysis of Wechsler Adult Intelligence Scale-III Similarities zero-point responses in 45 AD patients with varying numbers of VC, including diabetes, hypertension, and hypercholesterolemia. Errors were scored in set if the answer was vaguely related to how the word pair was alike (e.

Proteomics analysis reveals novel components in the detergent-insoluble subproteome in Alzheimer's disease.

Neurodegenerative diseases are often defined pathologically by the presence of protein aggregates. These aggregates, including amyloid plaques in Alzheimer's disease (AD), result from the abnormal accumulation and processing of proteins, and may ultimately lead to neuronal dysfunction and cell death. To date, conventional biochemical studies have revealed abundant core components in protein aggregates.

Implanted neural electrodes cause chronic, local inflammation that is correlated with local neurodegeneration.

Prosthetic devices that are controlled by intracortical electrodes recording one's 'thoughts' are a reality today, and no longer merely in the realm of science fiction. However, widespread clinical use of implanted electrodes is hampered by a lack of reliability in chronic recordings, independent of the type of electrodes used. One major hypothesis has been that astroglial scar electrically impedes the electrodes.

Is ApoE epsilon4 associated with cognitive functioning in African Americans diagnosed with Alzheimer Disease? An exploratory study.

Objective: The effect of the apolipoprotein epsilon4 allele (ApoE epsilon4) on cognitive performance in patients with probable Alzheimer disease (AD) has been studied in primarily Caucasian samples. The aim of this exploratory study was to examine whether the presence of ApoE epsilon4 is associated with cognitive performance in African American AD patients.

Methods: A cross-sectional, retrospective design was used to address the study objective.

Eye tracking during a visual paired comparison task as a predictor of early dementia.

The authors present findings from a behavioral task (visual paired comparison) using infrared eye-tracking that could potentially be useful in predicting the onset of Alzheimer's disease. Delay intervals of 2 seconds and 2 minutes were used between the initial viewing of a picture and when the picture was displayed alongside a novel picture. Eye-tracking revealed that at the 2-second delay, 6 patients with mild cognitive impairment, 15 matched control participants (normal control), and 4 neurological control participants with Parkinson's disease performed comparably, viewing the novel picture greater than 71% of the time.

Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction.

Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians.

SPE-39 family proteins interact with the HOPS complex and function in lysosomal delivery.

Yeast and animal homotypic fusion and vacuole protein sorting (HOPS) complexes contain conserved subunits, but HOPS-mediated traffic in animals might require additional proteins. Here, we demonstrate that SPE-39 homologues, which are found only in animals, are present in RAB5-, RAB7-, and RAB11-positive endosomes where they play a conserved role in lysosomal delivery and probably function via their interaction with the core HOPS complex. Although Caenorhabditis elegans spe-39 mutants were initially identified as having abnormal vesicular biogenesis during spermatogenesis, we show that these mutants also have disrupted processing of endocytosed proteins in oocytes and coelomocytes.

Effects of hypertension and hypercholesterolemia on cognitive functioning in patients with alzheimer disease.

This study investigated the relationship between the vascular comorbidities (VCs) of hypertension and hypercholesterolemia and the cognitive phenotype of Alzheimer disease (AD). Seventy-four AD patients underwent objective measurement of blood pressure and serum cholesterol levels, and they received a detailed neuropsychologic evaluation examining attention, memory, language, visuomotor/visuospatial skills, and executive functioning. Multiple regression analyses controlling for demographic variables, overall cognitive status, and the presence of diabetes/cardiac disease indicated that an increase in the number of VCs, but not their severity, was associated with poorer verbal and visual recall, visuoconstructive and spatial analysis, verbal reasoning, and set shifting.

Loss of LR11/SORLA enhances early pathology in a mouse model of amyloidosis: evidence for a proximal role in Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent form of dementia, resulting in progressive neuronal death and debilitating damage to brain loci that mediate memory and higher cognitive function. While pathogenic genetic mutations have been implicated in approximately 2% of AD cases, the proximal events that underlie the common, sporadic form of the disease are incompletely understood. Converging lines of evidence from human neuropathology, basic biology, and genetics have implicated loss of the multifunctional receptor LR11 (also known as SORLA and SORL1) in AD pathogenesis.

Development of a rapid screening instrument for mild cognitive impairment and undiagnosed dementia.

Mild cognitive impairment (MCI) often presages development of Alzheimer's disease (AD). We recently completed a cross-sectional study to test the hypothesis that a combination of a brief cognitive screening instrument (Mini-Cog) with a functional scale (Functional Activities Questionnaire; FAQ) would accurately identify individuals with MCI and undiagnosed dementia. The Mini-Cog consists of a clock drawing task and 3-item recall, and takes less than 5 minutes to administer.

Geographical differences in the occurrence of Alzheimer's disease mortality: United States versus Puerto Rico.

Since the implementation of the 10th International Classification of Disease in 1999, the trend in Alzheimer's disease mortality rate has not been reported. Here, the age-adjusted Alzheimer's disease mortality rate in Puerto Rico and United States from 1999 to 2004 was analyzed. The results showed an increasing trend in Alzheimer's disease mortality rate in both the United States and Puerto Rico.

Cognitive performance and plasma levels of homocysteine, vitamin B12, folate and lipids in patients with Alzheimer disease.

Background: Conflicting results have been reported on the association of plasma total homocysteine (tHcy) and cholesterol levels in Alzheimer disease (AD). The objective of this study was to determine the relationship between cognitive performance and plasma levels of tHcy and its biological determinants folate and vitamin B(12), and lipids in clinically diagnosed AD patients.

Methods: A cross-sectional database review was performed on two separate groups of patients (n = 191).

Association of GSK3B with Alzheimer disease and frontotemporal dementia.

Background: Deposits of abnormally hyperphosphorylated tau are a hallmark of several dementias, including Alzheimer disease (AD), and about 10% of familial frontotemporal dementia (FTD) cases are caused by mutations in the tau gene. As a known tau kinase, GSK3B is a promising candidate gene in the remaining cases of FTD and in AD, for which tau mutations have not been found.

Objective: To examine the promoter of GSK3B and all 12 exons, including the surrounding intronic sequence, in patients with FTD, patients with AD, and aged healthy subjects to identify single-nucleotide polymorphisms associated with disease.

Novel selective allosteric activator of the M1 muscarinic acetylcholine receptor regulates amyloid processing and produces antipsychotic-like activity in rats.

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].