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.

Thermodynamics of the lysozyme--salt interaction from calorimetric titrations.

It is well-known that the addition of salts influences the properties of proteins in solution. The essential nature of this phenomenon is far from being fully understood, partly due to the absence of the relevant thermodynamic information. To help fill this gap, in this work isothermal titration calorimetry (ITC) was employed to study the ion-lysozyme association in aqueous buffer solutions at pH = 4.

DNA duplex stability: the role of preorganized electrostatics.

The insertion of a DNA base moiety at the end of a DNA duplex to form a Watson-Crick or wobble pair during DNA annealing or replication is a step of fundamental biological importance. Therefore, we investigated the energetics of a formation of the terminal G x C, G x T, and G x A base pairs in DNA containing a 5'-dangling G adjacent to the base insertion point using differential scanning calorimetry and computer simulations. The energies calculated along classical molecular dynamics trajectories in aqueous solution were analyzed in the framework of linear-response approximation (LRA) to obtain relative free energies for the base insertion and their electrostatic, van der Waals, and preorganization components.

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.

Structural and thermodynamic characterization of Vibrio fischeri CcdB.

CcdB(Vfi) from Vibrio fischeri is a member of the CcdB family of toxins that poison covalent gyrase-DNA complexes. In solution CcdB(Vfi) is a dimer that unfolds to the corresponding monomeric components in a two-state fashion. In the unfolded state, the monomer retains a partial secondary structure.

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.

DHA diet reduces AD pathology in young APPswe/PS1 Delta E9 transgenic mice: possible gender effects.

Epidemiological and clinical trial findings suggest that consumption of docosahexaenoic acid (DHA) lowers the risk of Alzheimer's disease (AD). We examined the effects of short-term (3 months) DHA enriched diet on plaque deposition and synaptic defects in forebrain of young APPswe/PS1 Delta E9 transgenic (tg) and non-transgenic (ntg) mice. Gas chromatography revealed a significant increase in DHA concomitant with a decrease of arachidonic acid in both brain and liver in mice fed with DHA.

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.

Deficient high-affinity binding of Pittsburgh compound B in a case of Alzheimer's disease.

Radiolabeled Pittsburgh compound B (PIB) is a benzothiazole imaging agent that usually binds with high affinity, specificity, and stoichiometry to cerebral beta-amyloid (Abeta) in patients with Alzheimer's disease. Among a cohort of ten AD subjects examined postmortem, we describe a case of idiopathic, end-stage Alzheimer's disease with heavy Abeta deposition yet substantially diminished high-affinity binding of (3)H-PIB to cortical homogenates and unfixed cryosections. Cortical tissue samples were analyzed by immunohistochemistry, electron microscopy, ELISA, immunoblotting, MALDI-TOF mass spectrometry, in vitro (3)H-PIB binding and (3)H-PIB autoradiography.

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.

Energetics of MazG unfolding in correlation with its structural features.

MazG is a homodimeric alpha-helical protein that belongs to the superfamily of all-alpha NTP pyrophosphatases. Its function has been connected to the regulation of the toxin-antitoxin module mazEF, implicated in programmed growth arrest/cell death of Escherichia coli cells under conditions of amino acid starvation. The goal of the first detailed biophysical study of a member of the all-alpha NTP pyrophosphatase superfamily, presented here, is to improve molecular understanding of the unfolding of this type of proteins.

Driving forces of gyrase recognition by the addiction toxin CcdB.

Gyrase, an essential bacterial topoisomerase, is the target of several antibiotics (e.g. quinolones) as well as of bacterial toxin CcdB.

Alterations in cortical thickness and white matter integrity in mild cognitive impairment measured by whole-brain cortical thickness mapping and diffusion tensor imaging.

Background And Purpose: Mild cognitive impairment (MCI) is a risk factor for Alzheimer disease and can be difficult to diagnose because of the subtlety of symptoms. This study attempted to examine gray matter (GM) and white matter (WM) changes with cortical thickness analysis and diffusion tensor imaging (DTI) in patients with MCI and demographically matched comparison subjects to test these measurements as possible imaging markers for diagnosis.

Materials And Methods: Subjects with amnestic MCI (n = 10; age, 72.

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.

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.

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).

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].

Diverse polymorphism of G-quadruplexes as a kinetic phenomenon.

Knowledge of forces that drive conformational transitions of G-quadruplexes is crucial for understanding the molecular basis of several key cellular processes. It can only be acquired by combining structural, thermodynamic and kinetic information. Existing biophysical and structural evidences on polymorphism of intermolecular G-quadruplexes have shown that the formation of a number of these structures is a kinetically controlled process.

Dosimetry in an IMRT phantom designed for a remote monitoring program.

An accurate delivery of prescribed dose is essential to ensure the most successful outcome from advanced radiation treatments such as intensity modulated radiation therapy (IMRT). An anthropomorphic phantom was designed and constructed to conduct a remote-audit program for IMRT treatments. The accuracy of the dosimetry in the phantom was assessed by comparing the results obtained from different detectors with those from Monte Carlo calculations.

Fas-associated factor 1 and Parkinson's disease.

Fas-associated factor 1 or FAF1 is a Fas-binding protein implicated in apoptosis. FAF1 is the product of a gene at PARK 10 locus on chromosome 1p32, a locus associated with late-onset PD [Hicks, A.A.