Neuroscience and Neurobiology Commons^™

Selective Suppression Of The Α Isoform Of P38 Mapk Rescues Late-Stage Tau Pathology, Nicole Maphis, Shanya Jiang, Guixiang Xu, Olga N. Kokiko-Cochran, Saktimayee M. Roy, Linda J. Van Eldik, D. Martin Watterson, Bruce T. Lamb, Kiran Bhaskar

Sanders-Brown Center on Aging Faculty Publications

Background: Hyperphosphorylation and aggregation of tau protein are the pathological hallmarks of Alzheimer’s disease and related tauopathies. We previously demonstrated that the microglial activation induces tau hyperphosphorylation and cognitive impairment via activation of p38 mitogen-activated protein kinase (p38 MAPK) in the hTau mouse model of tauopathy that was deficient for microglial fractalkine receptor CX3CR1.

Method: We report an isoform-selective, brain-permeable, and orally bioavailable small molecule inhibitor of p38α MAPK (MW181) and its effects on tau phosphorylation in vitro and in hTau mice.

Results: First, pretreatment of mouse primary cortical neurons with MW181 completely blocked inflammation-induced p38α MAPK activation and AT8 …

Extracellular Vesicle-Associated Aβ Mediates Trans-Neuronal Bioenergetic And Ca2+-Handling Deficits In Alzheimer's Disease Models, Erez Eitan, Emmette R. Hutchison, Krisztina Marosi, James Comotto, Maja Mustapic, Saket M. Nigam, Caitlin Suire, Chinmoyee Maharana, Gregory A. Jicha, Dong Liu, Vasiliki Machairaki, Kenneth W. Witwer, Dimitrios Kapogiannis, Mark P. Mattson

Sanders-Brown Center on Aging Faculty Publications

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder in which aggregation-prone neurotoxic amyloid β-peptide (Aβ) accumulates in the brain. Extracellular vesicles (EVs), including exosomes, are small 50–150 nm membrane vesicles that have recently been implicated in the prion-like spread of self-aggregating proteins. Here we report that EVs isolated from AD patient cerebrospinal fluid and plasma, from the plasma of two AD mouse models, and from the medium of neural cells expressing familial AD presenilin 1 mutations, destabilize neuronal Ca²⁺ homeostasis, impair mitochondrial function, and sensitize neurons to excitotoxicity. EVs contain a relatively low amount of Aβ but have an …

Reduced Efficacy Of Anti-AΒ Immunotherapy In A Mouse Model Of Amyloid Deposition And Vascular Cognitive Impairment Comorbidity, Erica M. Weekman, Tiffany L. Sudduth, Carly N. Caverly, Timothy J. Kopper, Oliver W. Phillips, David K. Powell, Donna M. Wilcock

Sanders-Brown Center on Aging Faculty Publications

Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia behind Alzheimer's disease (AD). It is estimated that 40% of AD patients also have some form of VCID. One promising therapeutic for AD is anti-Aβ immunotherapy, which uses antibodies against Aβ to clear it from the brain. While successful in clearing Aβ and improving cognition in mice, anti-Aβ immunotherapy failed to reach primary cognitive outcomes in several different clinical trials. We hypothesized that one potential reason the anti-Aβ immunotherapy clinical trials were unsuccessful was due to this high percentage of VCID …

Age- And Sex-Related Changes In Fasting Plasma Glucose And Lipoprotein In Cynomolgus Monkeys, Feng Yue, Guodong Zhang, Rongping Tang, Zhouquan Zhang, Liqiong Teng, Zhiming Zhang

Neuroscience Faculty Publications

Background: The age-related dysfunction of glucose and lipid metabolism has a long-standing relationship with cardiovascular and neurodegenerative disease. However, the effects of metabolic dysfunction on men and women are different. Reasons for these sex differences remains unclear. Cynomolgus monkeys have been used, in the past, for the study of human metabolic diseases due to their biologically proximity to humans. Nevertheless, few studies to date have focused on both age- and sex-related differences in glucose and lipid metabolism. The present study was designed to specifically address these questions by using a large cohort of cynomolgus monkeys (N = 1,399) including …

Interaction Of Tau With The Rna-Binding Protein Tia1 Regulates Tau Pathophysiology And Toxicity, Tara Vanderweyde, Daniel J. Apicco, Katherine Youmans-Kidder, Peter E. A. Ash, Casey Cook, Edroaldo Lummertz Da Rocha, Karen Jansen-West, Alissa A. Frame, Allison Citro, John D. Leszyk, Pavel Ivanov, Jose F. Abisambra, Martin Steffen, Hu Li, Leonard Petrucelli, Benjamin Wolozin

Sanders-Brown Center on Aging Faculty Publications

Dendritic mislocalization of microtubule associated protein tau is a hallmark of tauopathies, but the role of dendritic tau is unknown. We now report that tau interacts with the RNA-binding protein (RBP) TIA1 in brain tissue, and we present the brain-protein interactome network for TIA1. Analysis of the TIA1 interactome in brain tissue from wild-type (WT) and tau knockout mice demonstrates that tau is required for normal interactions of TIA1 with proteins linked to RNA metabolism, including ribosomal proteins and RBPs. Expression studies show that tau regulates the distribution of TIA1, and tau accelerates stress granule (SG) formation. Conversely, TIA1 knockdown …

The Tnfα-Transgenic Rat: Hippocampal Synaptic Integrity, Cognition, Function, And Post-Ischemic Cell Loss, L. Creed Pettigrew, Richard J. Kryscio, Christopher M. Norris

Sanders-Brown Center on Aging Faculty Publications

The cytokine, tumor necrosis factor α (TNFα), is a key regulator of neuroinflammation linked to numerous neurodegenerative conditions and diseases. The present study used transgenic rats that overexpress a murine TNFα gene, under the control of its own promoter, to investigate the impact of chronically elevated TNFα on hippocampal synaptic function. Neuronal viability and cognitive recovery in TNFα Tg rats were also determined following an ischemic insult arising from reversible middle cerebral artery occlusion (MCAO). Basal CA3-CA1 synaptic strength, recorded in acute brain slices, was not significantly different between eight-week-old TNFα Tg rats and non-Tg rats. In contrast, slices from …

Proceedings Of The Third Annual Deep Brain Stimulation Think Tank: A Review Of Emerging Issues And Technologies, P. Justin Rossi, Aysegul Gunduz, Jack Judy, Linda Wilson, Andre Machado, James J Giordano, W. Jeff Elias, Marvin A. Rossi, Christopher L. Butson, Michael D. Fox, Cameron C. Mcintyre, Nader Pouratian, Nicole C. Swann, Coralie De Hemptinne, Robert E. Gross, Howard J. Chizeck, Michele Tagliati, Andres M. Lozano, Wayne Goodman, Jean-Philippe Langevin, Ron L. Alterman, Umer Akbar, Greg A. Gerhardt, Warren M. Grill, Mark Hallett, Todd Herrington, Jeffrey Herron, Craig Van Horne, Brian H. Kopell, Anthony E. Lang

Neuroscience Faculty Publications

The proceedings of the 3rd Annual Deep Brain Stimulation Think Tank summarize the most contemporary clinical, electrophysiological, imaging, and computational work on DBS for the treatment of neurological and neuropsychiatric disease. Significant innovations of the past year are emphasized. The Think Tank's contributors represent a unique multidisciplinary ensemble of expert neurologists, neurosurgeons, neuropsychologists, psychiatrists, scientists, engineers, and members of industry. Presentations and discussions covered a broad range of topics, including policy and advocacy considerations for the future of DBS, connectomic approaches to DBS targeting, developments in electrophysiology and related strides toward responsive DBS systems, and recent developments in sensor and …

AΒ40 Reduces P-Glycoprotein At The Blood-Brain Barrier Through The Ubiquitin-Proteasome Pathway, Anika M. S. Hartz, Yu Zhong, Andrea Wolf, Harry Levine Iii, David S. Miller, Björn Bauer

Sanders-Brown Center on Aging Faculty Publications

Failure to clear amyloid-β (Aβ) from the brain is in part responsible for Aβ brain accumulation in Alzheimer's disease (AD). A critical protein for clearing Aβ across the blood–brain barrier is the efflux transporter P-glycoprotein (P-gp) in the luminal plasma membrane of the brain capillary endothelium. P-gp is reduced at the blood–brain barrier in AD, which has been shown to be associated with Aβ brain accumulation. However, the mechanism responsible for P-gp reduction in AD is not well understood. Here we focused on identifying critical mechanistic steps involved in reducing P-gp in AD. We …

Pathological Tau Promotes Neuronal Damage By Impairing Ribosomal Function And Decreasing Protein Synthesis, Shelby Meier, Michelle Bell, Danielle N. Lyons, Jennifer Rodriguez-Rivera, Alexandria Ingram, Sarah N. Fontaine, Elizabeth Mechas, Jing Chen, Benjamin Wolozin, Harry Levine Iii, Haining Zhu, Jose F. Abisambra

Sanders-Brown Center on Aging Faculty Publications

One of the most common symptoms of Alzheimer's disease (AD) and related tauopathies is memory loss. The exact mechanisms leading to memory loss in tauopathies are not yet known; however, decreased translation due to ribosomal dysfunction has been implicated as a part of this process. Here we use a proteomics approach that incorporates subcellular fractionation and coimmunoprecipitation of tau from human AD and non-demented control brains to identify novel interactions between tau and the endoplasmic reticulum (ER). We show that ribosomes associate more closely with tau in AD than with tau in control brains, and that this abnormal association leads …