Insulin resistance, cognition, and functional brain network topology in older adults with obesity.

Objective: Cross-sectional data from a sample of older adults with obesity was used to determine how peripheral and neuronal insulin resistance (IR) relate to executive function and functional brain network topology.

Methods: Older adults (n=71) with obesity but without type 2 diabetes were included. Peripheral IR was quantified by HOMA2-IR.

Spatiotemporal relationships between neuronal, metabolic, and hemodynamic signals in the awake and anesthetized mouse brain.

Neurovascular coupling (NVC) and neurometabolic coupling (NMC) provide the basis for functional magnetic resonance imaging and positron emission tomography to map brain neurophysiology. While increases in neuronal activity are often accompanied by increases in blood oxygen delivery and oxidative metabolism, these observations are not the rule. This decoupling is important when interpreting brain network organization (e.

Alzheimer's and metabolism wed with IDO1.

Kynurenine pathway inhibition reverses deficits in Alzheimer's mouse models.

Exploratory Dual PET imaging of [F] fluorodeoxyglucose and [C]acetoacetate in type 2 diabetic nonhuman primates.

Despite recent advancements in imaging (amyloid-PET & tau-PET) and fluid (Aβ42/Aβ40 & Aβ42/ptau) biomarkers, the current standard for in vivo assessment of AD, diagnosis and prediction of Alzheimer's disease (AD) remains challenging. We demonstrated in nonhuman primates (NHP) that increased plasma and cerebrospinal fluid (CSF) glucose correlated with decreased CSF Aβ42 and CSF Aβ40, a hallmark of plaque promoting pathogenesis. Together, our findings demonstrate that altered glucose homeostasis and insulin resistance are associated with Aβ and amyloid in rodent and NHP models.

Exploring microtubule dynamics in Alzheimer's disease: Longitudinal assessment using [C]MPC-6827 PET imaging in rodent models of Alzheimer's-related pathology.

Introduction: Microtubule (MT) stability is crucial for proper neuronal function. Understanding MT dysregulation is critical for connecting amyloid beta (Aβ) and tau-based degenerative events and early changes in presymptomatic Alzheimer's disease (AD). Herein we present positron emission tomography (PET) imaging properties of our MT-PET radiotracer, [C]MPC-6827, in multiple established AD mouse models.

A unique multi-synaptic mechanism involving acetylcholine and GABA regulates dopamine release in the nucleus accumbens through early adolescence in male rats.

Adolescence is characterized by changes in reward-related behaviors, social behaviors, and decision-making. These behavioral changes are necessary for the transition into adulthood, but they also increase vulnerability to the development of a range of psychiatric disorders. Major reorganization of the dopamine system during adolescence is thought to underlie, in part, the associated behavioral changes and increased vulnerability.

Kir6.2-K channels alter glycolytic flux to modulate cortical activity, arousal, and sleep-wake homeostasis.

Unlabelled: Metabolism plays an important role in the maintenance of vigilance states (e.g. wake, NREM, and REM).

State of the Science on Brain Insulin Resistance and Cognitive Decline Due to Alzheimer's Disease.

Type 2 diabetes mellitus (T2DM) is common and increasing in prevalence worldwide, with devastating public health consequences. While peripheral insulin resistance is a key feature of most forms of T2DM and has been investigated for over a century, research on brain insulin resistance (BIR) has more recently been developed, including in the context of T2DM and non-diabetes states. Recent data support the presence of BIR in the aging brain, even in non-diabetes states, and found that BIR may be a feature in Alzheimer's disease (AD) and contributes to cognitive impairment.

Long-term dasatinib plus quercetin effects on aging outcomes and inflammation in nonhuman primates: implications for senolytic clinical trial design.

Cellular senescence increases with aging and results in secretion of pro-inflammatory factors that induce local and systemic tissue dysfunction. We conducted the first preclinical trial in a relevant middle-aged nonhuman primate (NHP) model to allow estimation of the main translatable effects of the senolytic combination dasatinib (D) and quercetin (Q), with and without caloric restriction (CR). A multi-systemic survey of age-related changes, including those on immune cells, adipose tissue, the microbiome, and biomarkers of systemic organ and metabolic health are reported.

KATP channels are necessary for glucose-dependent increases in amyloid-β and Alzheimer's disease-related pathology.

Elevated blood glucose levels, or hyperglycemia, can increase brain excitability and amyloid-β (Aβ) release, offering a mechanistic link between type 2 diabetes and Alzheimer's disease (AD). Since the cellular mechanisms governing this relationship are poorly understood, we explored whether ATP-sensitive potassium (KATP) channels, which couple changes in energy availability with cellular excitability, play a role in AD pathogenesis. First, we demonstrate that KATP channel subunits Kir6.

drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes.

Apolipoprotein E4 (APOE4) is the strongest risk allele associated with the development of late onset Alzheimer's disease (AD). Across the CNS, astrocytes are the predominant expressor of while also being critical mediators of neuroinflammation and cerebral metabolism. APOE4 has been consistently linked with dysfunctional inflammation and metabolic processes, yet insights into the molecular constituents driving these responses remain unclear.

Ethanol exposure alters Alzheimer's-related pathology, behavior, and metabolism in APP/PS1 mice.

Epidemiological studies identified alcohol use disorder (AUD) as a risk factor for Alzheimer's disease (AD), yet there is conflicting evidence on how alcohol use promotes AD pathology. In this study, a 10-week moderate two-bottle choice drinking paradigm was used to identify how chronic ethanol exposure alters amyloid-β (Aβ)-related pathology, metabolism, and behavior. Ethanol-exposed APPswe/PSEN1dE9 (APP/PS1) mice showed increased brain atrophy and an increased number of amyloid plaques.

Preliminary mechanistic insights of a brain-penetrant microtubule imaging PET ligand in a tau-knockout mouse model.

Background: Microtubules (MTs) are critical for cell structure, function, and survival. MT instability may contribute to Alzheimer's disease (AD) pathogenesis as evidenced by persistent negative regulation (phosphorylation) of the neuronal microtubule-associated protein tau. Hyperphosphorylated tau, not bound to MTs, forms intraneuronal pathology that correlates with dementia and can be tracked using positron emission tomography (PET) imaging.

Effect of ethanol and cocaine on [C]MPC-6827 uptake in SH-SY5Y cells.

Microtubules (MTs) are structural units in the cytoskeleton. In brain cells they are responsible for axonal transport, information processing, and signaling mechanisms. Proper function of these processes is critical for healthy brain functions.

Aging-related Alzheimer's disease-like neuropathology and functional decline in captive vervet monkeys (Chlorocebus aethiops sabaeus).

Age-related neurodegeneration characteristic of late-onset Alzheimer's disease (LOAD) begins in middle age, well before symptoms. Translational models to identify modifiable risk factors are needed to understand etiology and identify therapeutic targets. Here, we outline the evidence supporting the vervet monkey (Chlorocebus aethiops sabaeus) as a model of aging-related AD-like neuropathology and associated phenotypes including cognitive function, physical function, glucose handling, intestinal physiology, and CSF, blood, and neuroimaging biomarkers.

How Support of Early Career Researchers Can Reset Science in the Post-COVID19 World.

The COVID19 crisis has magnified the issues plaguing academic science, but it has also provided the scientific establishment with an unprecedented opportunity to reset. Shoring up the foundation of academic science will require a concerted effort between funding agencies, universities, and the public to rethink how we support scientists, with a special emphasis on early career researchers.

PET Imaging of [C]MPC-6827, a Microtubule-Based Radiotracer in Non-Human Primate Brains.

Dysregulation of microtubules is commonly associated with several psychiatric and neurological disorders, including addiction and Alzheimer's disease. Imaging of microtubules in vivo using positron emission tomography (PET) could provide valuable information on their role in the development of disease pathogenesis and aid in improving therapeutic regimens. We developed [C]MPC-6827, the first brain-penetrating PET radiotracer to image microtubules in vivo in the mouse brain.

The Interaction Between Sleep and Metabolism in Alzheimer's Disease: Cause or Consequence of Disease?

Alzheimer's disease (AD) is the most common form of dementia and affects over 45 million people worldwide. Both type-2-diabetes (T2D), a metabolic condition associated with aging, and disrupted sleep are implicated in the pathogenesis of AD, but how sleep and metabolism interact to affect AD progression remains unclear. In the healthy brain, sleep/wake cycles are a well-coordinated interaction between metabolic and neuronal activity, but when disrupted, are associated with a myriad of health-related issues, including metabolic syndrome, cardiovascular disease, T2D, and AD.

Type-2-Diabetes Alters CSF but Not Plasma Metabolomic and AD Risk Profiles in Vervet Monkeys.

Epidemiological studies suggest that individuals with type 2 diabetes (T2D) have a twofold to fourfold increased risk for developing Alzheimer's disease (AD), however, the exact mechanisms linking the two diseases are unknown. In both conditions, the majority of pathophysiological changes, including glucose and insulin dysregulation, insulin resistance, and AD-related changes in Aβ and tau, occur decades before the onset of clinical symptoms and diagnosis. In this study, we investigated the relationship between metabolic biomarkers associated with T2D and amyloid pathology including Aβ levels, from cerebrospinal fluid (CSF) and fasting plasma of healthy, pre-diabetic (PreD), and T2D vervet monkeys ().

Targeted Deletion of Hepatocyte Abca1 Increases Plasma HDL (High-Density Lipoprotein) Reverse Cholesterol Transport via the LDL (Low-Density Lipoprotein) Receptor.

Objective: The role of hepatocyte Abca1 (ATP binding cassette transporter A1) in trafficking hepatic free cholesterol (FC) into plasma versus bile for reverse cholesterol transport (RCT) is poorly understood. We hypothesized that hepatocyte Abca1 recycles plasma HDL-C (high-density lipoprotein cholesterol) taken up by the liver back into plasma, maintaining the plasma HDL-C pool, and decreasing HDL-mediated RCT into feces. Approach and Results: Chow-fed hepatocyte-specific Abca1 knockout (HSKO) and control mice were injected with human HDL radiolabeled with I-tyramine cellobiose (I-TC; protein) and H-cholesteryl oleate (H-CO).

Glucagon-Like Peptide-1 Cleavage Product Improves Cognitive Function in a Mouse Model of Down Syndrome.

Currently there is no effective therapy available for cognitive impairments in Down syndrome (DS), one of the most prevalent forms of intellectual disability in humans associated with the chromosomes 21 trisomy. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that maintains glucose homeostasis by stimulating insulin secretion. Its natural cleavage product GLP-1 (9-36) lacks insulinotropic effects and has a low binding affinity for GLP-1 receptors; thus, GLP-1 (9-36) has historically been identified as an inactive metabolite.

Slow wave sleep disruption increases cerebrospinal fluid amyloid-β levels.

See Mander et al. (doi:10.1093/awx174) for a scientific commentary on this article.