Epigenetic modulation of inflammation and synaptic plasticity promotes resilience against stress in mice.

Major depressive disorder is associated with abnormalities in the brain and the immune system. Chronic stress in animals showed that epigenetic and inflammatory mechanisms play important roles in mediating resilience and susceptibility to depression. Here, through a high-throughput screening, we identify two phytochemicals, dihydrocaffeic acid (DHCA) and malvidin-3'-O-glucoside (Mal-gluc) that are effective in promoting resilience against stress by modulating brain synaptic plasticity and peripheral inflammation.

Extracellular Tau Paired Helical Filaments Differentially Affect Tau Pathogenic Mechanisms in Mitotic and Post-Mitotic Cells: Implications for Mechanisms of Tau Propagation in the Brain.

The release of paired helical filaments (PHFs) from neurons into the extracellular space may contribute to the propagation of tau pathology across brain regions in Alzheimer's disease (AD) and other tauopathies. The majority of available mechanistic studies exploring the pathologic role of extracellular PHFs are conducted in proliferating cell lines. Here, we compare how extracellular PHFs induce tauopathy in mitotic cells and in post-mitotic brain neurons.

Biomarkers of Resilience in Stress Reduction for Caregivers of Alzheimer's Patients.

Caregiving for a dementia patient is associated with increased risk of psychological and physical health problems. We investigated whether a mindfulness-based stress reduction (MBSR) training course for caregivers that closely models the MBSR curriculum originally established by the Center of Mindfulness at the University of Massachusetts may improve the psychological resilience of non-professional caregivers of Alzheimer's disease patients. Twenty adult non-professional caregivers of dementia patients participated in an 8-week MBSR training course.

In Silico Modeling of Novel Drug Ligands for Treatment of Concussion Associated Tauopathy.

The objective of this study was to develop an in silico screening model for characterization of potential novel ligands from commercial drug libraries able to functionally activate certain olfactory receptors (ORs), which are members of the class A rhodopsin-like family of G protein couple receptors (GPCRs), in the brain of murine models of concussion. We previously found that concussions may significantly influence expression of certain ORs, for example, OR4M1 in subjects with a history of concussion/traumatic brain injury (TBI). In this study, we built a 3-D OR4M1 model and used it in in silico screening of potential novel ligands from commercial drug libraries.

Novel application of brain-targeting polyphenol compounds in sleep deprivation-induced cognitive dysfunction.

Sleep deprivation produces deficits in hippocampal synaptic plasticity and hippocampal-dependent memory storage. Recent evidence suggests that sleep deprivation disrupts memory consolidation through multiple mechanisms, including the down-regulation of the cAMP-response element-binding protein (CREB) and of mammalian target of rapamycin (mTOR) signaling. In this study, we tested the effects of a Bioactive Dietary Polyphenol Preparation (BDPP), comprised of grape seed polyphenol extract, Concord grape juice, and resveratrol, on the attenuation of sleep deprivation-induced cognitive impairment.

IVIG immunotherapy protects against synaptic dysfunction in Alzheimer's disease through complement anaphylatoxin C5a-mediated AMPA-CREB-C/EBP signaling pathway.

Background: Complement component C5-derived C5a locally generated in the brain has been shown to protect against glutamate-induced neuronal apoptosis and beta-amyloid (Aβ) toxicity, but the mechanism is not clear. In this study, we tested the hypothesis that C5a influences upstream signal transduction pathways associated with cAMP-response element-binding protein (CREB) activation, in which alterations of CREB levels are associated with cognitive deterioration in AD.

Methods: CREB signaling pathway, synaptic plasticity and cognitive function were studied in C5a receptor knockout mice (C5aR(-/-)), C5a over expressing mice (C5a/GFAP) and in Tg2576 mice, an AD mouse model.

Decreased level of olfactory receptors in blood cells following traumatic brain injury and potential association with tauopathy.

Traumatic brain injury (TBI) is a leading cause of death and disability among children and young adults in the United States. In this study, we explored whether changes in the gene expression profile of peripheral blood mononuclear cells (PBMC) may provide a clinically assessable "window" into the brain, reflecting molecular alterations following TBI that might contribute to the onset and progression of TBI clinical complications. We identified three olfactory receptor (OR) TBI biomarkers that are aberrantly down-regulated in PBMC specimens from TBI subjects.

Insulin receptor expression and activity in the brains of nondiabetic sporadic Alzheimer's disease cases.

We investigated the contents of the insulin receptor-beta subunit (IRβ) and [Tyr1162/1163]-phosphorylated IRβ as surrogate indices of total IR content and IR activation in postmortem hippocampal formation brain specimens from nondiabetic sporadic Alzheimer's disease (AD) cases. We found no significant changes in the brain contents of total IRβ or [Tyr1162/1163]-phosphorylated IRβ, suggesting normal IR content and activation in the brains of nondiabetic sporadic AD cases. Moreover, total IRβ and [Tyr1162/1163]-phosphorylated IRβ levels in the hippocampal formation are not correlated with the severity of amyloid or tau-neuropathology.

Elevated plasma MCP-1 concentration following traumatic brain injury as a potential "predisposition" factor associated with an increased risk for subsequent development of Alzheimer's disease.

We explored whether changes in the expression profile of peripheral blood plasma proteins may provide a clinical, readily accessible "window" into the brain, reflecting molecular alterations following traumatic brain injury (TBI) that might contribute to TBI complications. We recruited fourteen TBI and ten control civilian participants for the study, and also analyzed banked plasma specimens from 20 veterans with TBI and 20 control cases. Using antibody arrays and ELISA assays, we explored differentially-regulated protein species in the plasma of TBI compared to healthy controls from the two independent cohorts.

Peroxisome proliferator activator receptor gamma coactivator-1alpha (PGC-1α) improves motor performance and survival in a mouse model of amyotrophic lateral sclerosis.

Background: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects spinal cord and cortical motor neurons. An increasing amount of evidence suggests that mitochondrial dysfunction contributes to motor neuron death in ALS. Peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α) is a principal regulator of mitochondrial biogenesis and oxidative metabolism.

Grape seed polyphenolic extract as a potential novel therapeutic agent in tauopathies.

Abnormal misfoldings of the microtubule-associated protein tau, leading to the aggregation of tau into paired helical filaments that are ultimately deposited as neurofibrillary tangles, is a key neuropathologic feature of a number of neurodegenerative disorders collectively referred to as tauopathies. We recently observed that a particular grape seed polyphenolic extract (GSPE), namely, Meganatural-Az may attenuate the generation and stability of misfolded proteins. We hypothesized that Meganatural-Az GSPE might also attenuate tau protein misfolding that leads to the generation of tau filamentary aggregates that are critical for the initiation and progression of neurodegeneration and/or cognitive dysfunctions in tauopathies.

Caloric intake and Alzheimer's disease. Experimental approaches and therapeutic implications.

Alzheimer's disease (AD) is a rapidly growing public health concern with potentially devastating effects. Presently, there are no known cures or effective preventive strategies. While genetic factors are relevant in early-onset cases, they appear to play less of a role in late-onset sporadic AD cases, the most common form of AD.

Caspase gene expression in the brain as a function of the clinical progression of Alzheimer disease.

Background: Caspase gene expression has previously been reported in terminal Alzheimer disease (AD) brain, but, currently, little is known about the temporal pattern of caspase gene expression relative to the onset and clinical progression of AD.

Objective: To derive a profile of caspase gene expression and proapoptotic indexes as a function of the clinical and neuropathologic progression of AD dementia.

Setting And Patients: Postmortem survey of nursing home patients characterized clinically by Clinical Dementia Rating (CDR) and neuropathologically by Consortium to Establish a Registry for Alzheimer's Disease criteria.

Cyclooxygenase-2 promotes amyloid plaque deposition in a mouse model of Alzheimer's disease neuropathology.

Several epidemiologic studies have reported that cyclooxygenase (COX) inhibitors prevent/delay the onset of Alzheimer's disease (AD). Recent experimental studies suggest that these compounds can also diminish amyloid-beta (Abeta) neuropathology in rodent models of AD. To explore the relationship of COX expression to Abeta neuropathology, we crossed mice expressing both mutant amyloid precursor protein [K670N/M671L (APP(swe)] and mutant PS1 (A246E) with mice expressing human COX-2 selectively in neurons.