Cross-disease modeling of peripheral blood identifies biomarkers of type 2 diabetes predictive of Alzheimer's disease.

Type 2 diabetes (T2D) is a significant risk factor for Alzheimer's disease (AD). Despite multiple studies reporting this connection, the mechanism by which T2D exacerbates AD is poorly understood. It is challenging to design studies that address co-occurring and comorbid diseases, limiting the number of existing evidence bases.

Cross-Species Modeling Identifies Gene Signatures in Type 2 Diabetes Mouse Models Predictive of Inflammatory and Estrogen Signaling Pathways Associated with Alzheimer's Disease Outcomes in Humans.

Alzheimer's disease (AD), the predominant form of dementia, is influenced by several risk factors, including type 2 diabetes (T2D), a metabolic disorder characterized by the dysregulation of blood sugar levels. Despite mouse and human studies reporting this connection between T2D and AD, the mechanism by which T2D contributes to AD pathobiology is not well understood. A challenge in understanding mechanistic links between these conditions is that evidence between mouse and human experimental models must be synthesized, but translating between these systems is difficult due to evolutionary distance, physiological differences, and human heterogeneity.

Alcohol consumption confers lasting impacts on prefrontal cortical neuron intrinsic excitability and spontaneous neurotransmitter signaling in the aging brain in mice.

Both alcohol use disorder (AUD) and cognitive decline include disruption in the balance of excitation and inhibition in the cortex, but the potential role of alcohol use on excitation and inhibition on the aging brain is unclear. We examined the effect of moderate voluntary binge alcohol consumption on the aged, pre-disease neuronal environment by measuring intrinsic excitability and spontaneous neurotransmission on prefrontal cortical pyramidal (excitatory, glutamatergic) and non-pyramidal (inhibitory, GABAergic) neurons following a prolonged period of abstinence from alcohol in mice. Results highlight that binge alcohol consumption has lasting impacts on the electrophysiological properties of prefrontal cortical neurons.

Microglial Drivers of Alzheimer's Disease Pathology: An Evolution of Diverse Participating States.

Microglia, the resident immune-competent cells of the brain, become dysfunctional in Alzheimer's disease (AD), and their aberrant immune responses contribute to the accumulation of pathological proteins and neuronal injury. Genetic studies implicate microglia in the development of AD, prompting interest in developing immunomodulatory therapies to prevent or ameliorate disease. However, microglia take on diverse functional states in disease, playing both protective and detrimental roles in AD, which largely overlap and may shift over the disease course, complicating the identification of effective therapeutic targets.

Differential responses of primary neuron-secreted MCP-1 and IL-9 to type 2 diabetes and Alzheimer's disease-associated metabolites.

Type 2 diabetes (T2D) is implicated as a risk factor for Alzheimer's disease (AD), the most common form of dementia. In this work, we investigated neuroinflammatory responses of primary neurons to potentially circulating, blood-brain barrier (BBB) permeable metabolites associated with AD, T2D, or both. We identified nine metabolites associated with protective or detrimental properties of AD and T2D in literature (lauric acid, asparagine, fructose, arachidonic acid, aminoadipic acid, sorbitol, retinol, tryptophan, niacinamide) and stimulated primary mouse neuron cultures with each metabolite before quantifying cytokine secretion via Luminex.

Everolimus alleviates CD4 T cell inflammation by regulating autophagy and cellular redox homeostasis.

Aging is associated with the onset and progression of multiple diseases, which limit health span. Chronic low-grade inflammation in the absence of overt infection is considered the simmering source that triggers age-associated diseases. Failure of many cellular processes during aging is mechanistically linked to inflammation; however, the overall decline in the cellular homeostasis mechanism of autophagy has emerged as one of the top and significant inducers of inflammation during aging, frequently known as inflammaging.

MODERATE ALCOHOL CONSUMPTION INDUCES LASTING IMPACTS ON PREFRONTAL CORTICAL SIGNALING IN MICE.

Both alcohol use disorder (AUD) and Alzheimer's Disease and Related Dementias (ADRD) appear to include disruption in the balance of excitation and inhibition in the cortex, but their potential interactions are unclear. We examined the effect of moderate voluntary binge alcohol consumption on the aged, pre-disease neuronal environment by measuring intrinsic excitability and spontaneous neurotransmission on prefrontal cortical pyramidal (excitatory, glutamatergic) and non-pyramidal (inhibitory, GABAergic) neurons following a prolonged period of abstinence from alcohol in mice. Results highlight that binge alcohol consumption has lasting impacts on the electrophysiological properties of prefrontal cortical neurons.

Cytokine expression patterns predict suppression of vulnerable neural circuits in a mouse model of Alzheimer's disease.

Alzheimer's disease is a neurodegenerative disorder characterized by progressive amyloid plaque accumulation, tau tangle formation, neuroimmune dysregulation, synapse an neuron loss, and changes in neural circuit activation that lead to cognitive decline and dementia. Early molecular and cellular disease-instigating events occur 20 or more years prior to presentation of symptoms, making them difficult to study, and for many years amyloid-β, the aggregating peptide seeding amyloid plaques, was thought to be the toxic factor responsible for cognitive deficit. However, strategies targeting amyloid-β aggregation and deposition have largely failed to produce safe and effective therapies, and amyloid plaque levels poorly correlate with cognitive outcomes.

Differential responses of primary neuron-secreted MCP-1 and IL-9 to type 2 diabetes and Alzheimer's disease-associated metabolites.

Type 2 diabetes (T2D) is implicated as a risk factor for Alzheimer's disease (AD), the most common form of dementia. In this work, we investigated neuroinflammatory responses of primary neurons to potentially circulating, blood-brain barrier (BBB) permeable metabolites associated with AD, T2D, or both. We identified nine metabolites associated with protective or detrimental properties of AD and T2D in literature (lauric acid, asparagine, fructose, arachidonic acid, aminoadipic acid, sorbitol, retinol, tryptophan, niacinamide) and stimulated primary mouse neuron cultures with each metabolite before quantifying cytokine secretion via Luminex.

Dynamic neuroinflammatory profiles predict Alzheimer's disease pathology in microglia-containing cerebral organoids.

Neuroinflammation and the underlying dysregulated immune responses of microglia actively contribute to the progression and, likely, the initiation of Alzheimer's disease (AD). Fine-tuned therapeutic modulation of immune dysfunction to ameliorate disease cannot be achieved without the characterization of diverse microglial states that initiate unique, and sometimes contradictory, immune responses that evolve over time in chronic inflammatory environments. Because of the functional differences between human and murine microglia, untangling distinct, disease-relevant reactive states and their corresponding effects on pathology or neuronal health may not be possible without the use of human cells.

STAT3 modulates CD4 T mitochondrial dynamics and function in aging.

Aging promotes numerous intracellular changes in T cells that impact their effector function. Our data show that aging promotes an increase in the localization of STAT3 to the mitochondria (mitoSTAT3), which promotes changes in mitochondrial dynamics and function and T-cell cytokine production. Mechanistically, mitoSTAT3 increased the activity of aging T-cell mitochondria by increasing complex II.

Amyloid-β Pathology-Specific Cytokine Secretion Suppresses Neuronal Mitochondrial Metabolism.

Introduction: Neuroinflammation and metabolic dysfunction are early alterations in Alzheimer's disease (AD) brain that are thought to contribute to disease onset and progression. Glial activation due to protein deposition results in cytokine secretion and shifts in brain metabolism, which have been observed in AD patients. However, the mechanism by which this immunometabolic feedback loop can injure neurons and cause neurodegeneration remains unclear.

Alzheimer's disease-specific cytokine secretion suppresses neuronal mitochondrial metabolism.

Introduction: Neuroinflammation and metabolic dysfunction are early alterations in Alzheimer's disease brain that are thought to contribute to disease onset and progression. Glial activation due to protein deposition results in cytokine secretion and shifts in brain metabolism, which have been observed in Alzheimer's disease patients. However, the mechanism by which this immunometabolic feedback loop can injure neurons and cause neurodegeneration remains unclear.

Apolipoprotein E ε4 modulates astrocyte neuronal support functions in the presence of amyloid-β.

Apolipoprotein E (APOE) is a lipid transporter produced predominantly by astrocytes in the brain. The ε4 variant of APOE (APOE4) is the strongest and most common genetic risk factor for Alzheimer's disease (AD). Although the molecular mechanisms of this increased risk are unclear, APOE4 is known to alter immune signaling and lipid and glucose metabolism.

Predictive link between systemic metabolism and cytokine signatures in the brain of apolipoprotein E ε4 mice.

The ε4 variant of apolipoprotein E (APOE) is the strongest and most common genetic risk factor for Alzheimer's disease (AD). While the mechanism of conveyed risk is incompletely understood, promotion of inflammation, dysregulated metabolism, and protein misfolding and aggregation are contributors to accelerating disease. Here we determined the concurrent effects of systemic metabolic changes and brain inflammation in young (3-month-old) and aged (18-month-old) male and female mice carrying the APOE4 gene.

Monosialotetrahexosylganglioside Promotes Early Aβ42 Oligomer Formation and Maintenance.

The aggregation of the amyloid beta (Aβ) peptide is associated with Alzheimer's disease (AD) pathogenesis. Cell membrane composition, especially monosialotetrahexosylganglioside (GM1), is known to promote the formation of Aβ fibrils, yet little is known about the roles of GM1 in the early steps of Aβ oligomer formation. Here, by using GM1-contained liposomes as a mimic of the neuronal cell membrane, we demonstrate that GM1 is a critical trigger of Aβ oligomerization and aggregation.

Astrocytic Propagation of Tau in the Context of Alzheimer's Disease.

More than 6 million Americans are currently living with Alzheimer's disease (AD), and the incidence is growing rapidly with our aging population. Numerous therapeutics have failed to make it to the clinic, potentially due to a focus on presumptive pathogenic proteins instead of cell-type-specific signaling mechanisms. The tau propagation hypothesis that inter-neuronal tau transfer drives AD pathology has recently garnered attention, as accumulation of pathological tau in the brain has high clinical significance in correlating with progression of cognitive AD symptoms.

Pathogen-specific antimicrobials engineered de novo through membrane-protein biomimicry.

Precision antimicrobials aim to kill pathogens without damaging commensal bacteria in the host, and thereby cure disease without antibiotic-associated dysbiosis. Here we report the de novo design of a synthetic host defence peptide that targets a specific pathogen by mimicking key molecular features of the pathogen's channel-forming membrane proteins. By exploiting physical and structural vulnerabilities within the pathogen's cellular envelope, we designed a peptide sequence that undergoes instructed tryptophan-zippered assembly within the mycolic acid-rich outer membrane of Mycobacterium tuberculosis to specifically kill the pathogen without collateral toxicity towards lung commensal bacteria or host tissue.

Neurovascular coupling and bilateral connectivity during NREM and REM sleep.

To understand how arousal state impacts cerebral hemodynamics and neurovascular coupling, we monitored neural activity, behavior, and hemodynamic signals in un-anesthetized, head-fixed mice. Mice frequently fell asleep during imaging, and these sleep events were interspersed with periods of wake. During both NREM and REM sleep, mice showed large increases in cerebral blood volume ([HbT]) and arteriole diameter relative to the awake state, two to five times larger than those evoked by sensory stimulation.

Sexually dimorphic impact of the iron-regulating gene, , on survival in glioblastoma.

Background: The median survival for patients with glioblastoma (GBM), the most common primary malignant brain tumor in adults, has remained approximately 1 year for more than 2 decades. Recent advances in the field have identified GBM as a sexually dimorphic disease. It is less prevalent in females and they have better survival compared to males.

Metformin Enhances Autophagy and Normalizes Mitochondrial Function to Alleviate Aging-Associated Inflammation.

Age is a non-modifiable risk factor for the inflammation that underlies age-associated diseases; thus, anti-inflammaging drugs hold promise for increasing health span. Cytokine profiling and bioinformatic analyses showed that Th17 cytokine production differentiates CD4 T cells from lean, normoglycemic older and younger subjects, and mimics a diabetes-associated Th17 profile. T cells from older compared to younger subjects also had defects in autophagy and mitochondrial bioenergetics that associate with redox imbalance.

Coagulopathy signature precedes and predicts severity of end-organ heat stroke pathology in a mouse model.

Background: Immune challenge is known to increase heat stroke risk, although the mechanism of this increased risk is unclear.

Objectives: We sought to understand the effect of immune challenge on heat stroke pathology.

Patients/methods: Using a mouse model of classic heat stroke, we examined the impact of prior viral or bacterial infection on hematological aspects of recovery.

Fatty Acid Metabolites Combine with Reduced β Oxidation to Activate Th17 Inflammation in Human Type 2 Diabetes.

Mechanisms that regulate metabolites and downstream energy generation are key determinants of T cell cytokine production, but the processes underlying the Th17 profile that predicts the metabolic status of people with obesity are untested. Th17 function requires fatty acid uptake, and our new data show that blockade of CPT1A inhibits Th17-associated cytokine production by cells from people with type 2 diabetes (T2D). A low CACT:CPT1A ratio in immune cells from T2D subjects indicates altered mitochondrial function and coincides with the preference of these cells to generate ATP through glycolysis rather than fatty acid oxidation.

β-Methylamino-L-alanine substitution of serine in SOD1 suggests a direct role in ALS etiology.

Exposure to the environmental toxin β-methylamino-L-alanine (BMAA) is linked to amyotrophic lateral sclerosis (ALS), but its disease-promoting mechanism remains unknown. We propose that incorporation of BMAA into the ALS-linked protein Cu,Zn superoxide dismutase (SOD1) upon translation promotes protein misfolding and aggregation, which has been linked to ALS onset and progression. Using molecular simulation and predictive energetic computation, we demonstrate that substituting any serine with BMAA in SOD1 results in structural destabilization and aberrant dynamics, promoting neurotoxic SOD1 aggregation.