Life Sciences Commons^™

Circadian Modulation Of Astrocyte Morphology And Synaptic Transmission, Saad Ahmad

Biological Sciences

The circadian rhythm affects behavior and physiology in many animal species. Our previous work in mice showed that within the hippocampus, a subordinate circadian oscillator, astrocytes change their proximity to excitatory synapses. Here we obtain 3D reconstructions of biocytin-filled hippocampal astrocytes processed with protein retention expansion microscopy and imaged using two-photon laser scanning microscopy. Our findings identify the subtle changes in astrocyte morphologies that encode information about time-of-day in hippocampal astrocytes. These findings shed light on fundamental mechanisms that allow the function of hippocampal circuits to adapt to different times of the day. This will help us understand how structural …

Importin-Mediated Pathological Tau Nuclear Translocation Causes Disruption Of The Nuclear Lamina, Tdp-43 Mislocalization And Cell Death, Robert F. Candia, Leah S. Cohen, Viktoriya Morozova, Christopher Corbo, Alejandra D. Alonso

Publications and Research

Tau is a cytosolic protein that has also been observed in the nucleus, where it has multiple proposed functions that are regulated by phosphorylation. However, the mechanism underlying the nuclear import of tau is unclear, as is the contribution of nuclear tau to the pathology of tauopathies. We have previously generated a pathological form of tau, PH-tau (pseudophosphorylation mutants S199E, T212E, T231E, and S262E) that mimics AD pathological behavior in cells, Drosophila, and a mouse model. Here, we demonstrated that PH-tau translocates into the nucleus of transiently transfected HEK-293 cells, but wildtype tau does not. We identified a putative …

Transcriptome Analyses In Bv2 Microglial Cells Following Treatment With Amino-Terminal Fragments Of Apolipoprotein E, Tanner B. Pollock, Giovan N. Cholico, Tarun Suresh, Erica S. Stewart, Madyson M. Mccarthy, Troy T. Rohn

Biology Faculty Publications and Presentations

Despite the fact that harboring the apolipoprotein E4 (APOE4) allele represents the single greatest risk factor for late-onset Alzheimer’s disease (AD), the exact mechanism by which ApoE4 contributes to disease progression remains unknown. Recently, we demonstrated that a 151 amino-terminal fragment of ApoE4 (nApoE4_1–151) localizes within the nucleus of microglia in the human AD brain and traffics to the nucleus causing toxicity in BV2 microglia cells. In the present study, we examined in detail what genes may be affected following treatment by nApoE4_1–151. Transcriptome analyses in BV2 microglial cells following sublethal treatment with nApoE4 …

Deep Multilayer Brain Proteomics Identifies Molecular Networks In Alzheimer's Disease Progression, Bing Bai, Xusheng Wang, Yuxin Li, Ping-Chung Chen, Kaiwen Yu, Kaushik Kumar Dey, Jay M. Yarbro, Xian Han, Brianna M. Lutz, Shuquan Rao, Yun Jiao, Jeffrey M. Sifford, Jonghee Han, Minghui Wang, Haiyan Tan, Timothy I. Shaw, Ji-Hoon Cho, Suiping Zhou, Hong Wang, Mingming Niu, Ariana Mancieri, Kaitlynn A. Messler, Xiaojun Sun, Zhiping Wu, Vishwajeeth Pagala, Anthony A. High, Wenjian Bi, Hui Zhang, Hongbo Chi, Vahram Haroutunian, Bin Zhang, Thomas G. Beach, Gang Yu, Junmin Peng

Biology Faculty Publications

Alzheimer's disease (AD) displays a long asymptomatic stage before dementia. We characterize AD stage-associated molecular networks by profiling 14,513 proteins and 34,173 phosphosites in the human brain with mass spectrometry, highlighting 173 protein changes in 17 pathways. The altered proteins are validated in two independent cohorts, showing partial RNA dependency. Comparisons of brain tissue and cerebrospinal fluid proteomes reveal biomarker candidates. Combining with 5xFAD mouse analysis, we determine 15 Aβ-correlated proteins (e.g., MDK, NTN1, SMOC1, SLIT2, and HTRA1). 5xFAD shows a proteomic signature similar to symptomatic AD but exhibits activation of autophagy and interferon response and lacks human-specific deleterious events, …

A Role Of Vitamin B2 In Reducing Amyloid-Beta Toxicity In A Caenorhabditis Elegans Alzheimer’S Disease Model, Muhammad Tukur Ameen

Electronic Theses and Dissertations

Alzheimer’s disease (AD) is associated with amyloid-beta peptide deposition and loss of mitochondrial function. Using a transgenic C. elegans AD worm model expressing amyloid-beta in body wall muscle, we determined that supplementation with either of the forms of vitamin B₂, flavin mononucleotide (FMN) or flavin adenine dinucleotide (FAD) protected against amyloid-beta mediated paralysis. FMN and FAD were then assayed to determine effects on ATP, oxygen consumption, and reactive oxygen species (ROS) with these compounds not significantly improving any of these mitochondrial bioenergetic functions. Knockdown of the daf-16/FOXO transcriptional regulator or the FAD synthase enzyme completely abrogated the …

The Role Of Gene Therapy In Neurodegenerative Disease Treatment, Elaina Bohanon

Senior Honors Projects

No abstract provided.

Is Detection Of Preclinical Alzheimer’S Disease Possible?, Shana Brawer

The Science Journal of the Lander College of Arts and Sciences

No abstract provided.

App Regulates Microglial Phenotype In A Mouse Model Of Alzheimer's Disease, Gunjan D. Manocha, Angela M. Floden, Keiko Rausch, Joshua A. Kulas, Brett A. Mcgregor, Lalida Rojanathammanee, Kelley R. Puig, Kendra L. Puig, Sanjib Karki, Michael R. Nichols, Diane C. Darland, James E. Porter, Colin K. Combs

Biology Faculty Publications

Prior work suggests that amyloid precursor protein (APP) can function as a proinflammatory receptor on immune cells, such as monocytes and microglia. Therefore, we hypothesized that APP serves this function in microglia during Alzheimer's disease. Although fibrillar amyloid β (Aβ)-stimulated cytokine secretion from both wild-type and APP knock-out (mAPP−/−) microglial cultures, oligomeric Aβ was unable to stimulate increased secretion from mAPP−/− cells. This was consistent with an ability of oligomeric Aβ to bind APP. Similarly, intracerebroventricular infusions of oligomeric Aβ produced less microgliosis in mAPP−/− mice compared with wild-type mice. The mAPP−/− mice crossed to an APP/PS1 transgenic mouse line …

Effect Of Cntf Derived Peptide, P021 On Cognition And Pathology In 3xtg-Ad Mouse Model Of Alzheimer's Disease, Narjes Baazaoui

Dissertations, Theses, and Capstone Projects

Studies described in this thesis deal with the preventive effects of a neurogenic/neurotropic peptidergic compound, P021, on neurogenesis and synaptic deficits, neurodegeneration, cognitive impairment, and Ab and tau pathologies in a 3xTg-AD mouse model of Alzheimer’s disease (AD).

Background: AD is a chronic progressive neurodegenerative disease. Its multifactorial nature and the heterogeneity make its treatment especially challenging. Although it is a major burden in society, at present there is no drug that can stop or slow down the progression of the disease. Currently, the only available treatments are symptomatic and for mild to severe stages. The development of a drug …

Proteolytic Cleavage Of Apolipoprotein E In The Down Syndrome Brain, Ryan J. Day, Katie L. Mccarty, Kayla E. Ockerse, Elizabeth Head, Troy T. Rohn

Biology Faculty Publications and Presentations

Down syndrome (DS) is one of the most common genetic causes of intellectual disability and is characterized by a number of behavioral as well as cognitive symptoms. Many of the neuropathological features of early-onset Alzheimer’s disease (AD) including senile plaques and neurofibrillary tangles (NFTs) are also present in people with DS as a result of triplication of the amyloid precursor gene on chromosome 21. Evidence suggests that harboring one or both apolipoprotein E4 (APOE4) alleles may increase the risk for AD due to the proteolytic cleavage of apoE4 and a subsequent loss of function. To investigate a role …

Characterization Of Continuously Oscillating Neurons (Cons) Of The Medial Septum Of Rats, Nadia Noel Carreon

Theses and Dissertations - UTB/UTPA

Theta oscillation is the largest extracellular synchronous signal that can be recorded from the mammalian brain. It is known to influence information retention in the hippocampus, which plays a key role in declarative memory, recognition memory, working memory, and spatial memory. The theta oscillation field frequency is between 3 and 12 Hz and is present during exploratory behavior and sleep in rodents. Theta rhythm in the hippocampus is postulated to be produced by the rhythmical activity of pacemaking cells in the medial septumvertical limb of the diagonal band of Broca (MS-vDBB). Previous work in our laboratory demonstrated the existence of …

Proteolytic Cleavage Of Apolipoprotein E4 As The Keystone For The Heightened Risk Associated With Alzheimer’S Disease, Troy T. Rohn

Biology Faculty Publications and Presentations

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by microscopic lesions consisting of beta-amyloid plaques and neurofibrillary tangles (NFTs). The majority of cases are defined as sporadic and are likely caused by a combination of both genetic and environmental factors. Of the genetic risk factors identified, the 34 kDa protein, apolipoprotein (apo) E4, is of significant importance as APOE4 carriers account for 65%–80% of all AD cases. Although apoE4 plays a normal role in lipoprotein transport, how it contributes to AD pathogenesis is currently unknown. One potential mechanism by which apoE4 contributes to disease risk is its propensity to …

Delayed Amyloid Plaque Deposition And Behavioral Deficits In Outcrossed Aβpp/Ps1 Mice, Brian A. Couch, Meghan E. Kerrisk, Adam C. Kaufman, Haakon B. Nygaard, Stephen M. Strittmatter, Anthony J. Koleske

School of Biological Sciences: Faculty Publications

Alzheimer’s disease (AD) is a progressive neurodegenerative dementia characterized by amyloid plaque accumulation, synapse/dendrite loss, and cognitive impairment. Transgenic mice expressing mutant forms of amyloid-β precursor protein (AβPP) and presenilin-1 (PS1) recapitulate several aspects of this disease and provide a useful model system for studying elements of AD progression. AβPP/PS1 mice have been previously shown to exhibit behavioral deficits and amyloid plaque deposition between 4–9 months of age. We crossed AβPP/PS1 animals with mice of a mixed genetic background (C57BL/6 × 129/SvJ) and investigated the development of AD-like features in the resulting outcrossed mice. The onset of memory-based behavioral impairment …

Aβ Alters The Dna Methylation Status Of Cell-Fate Genes In An Alzheimer’S Disease Model, Gary D. Isaacs, Noor Taher, Courtney Mckenzie, Rebecca Garrett, Matthew Baker, Nena Fox

Faculty Publications and Presentations

Alzheimer’s disease (AD) is characterized by neurofibrillary tangles and extracellular amyloid-β plaques (Aβ). Despite ongoing research, some ambiguity remains surrounding the role of Aβ in the pathogenesis of this neurodegenerative disease. While several studies have focused on the mutations associated with AD, our understanding of the epigenetic contributions to the disease remains less clear. To that end, we determined the changes in DNA methylation in differentiated human neurons with and without Aβ treatment. We isolated the DNA from neurons treated with Aβ or vehicle, and digested the two samples with either a methylation-sensitive (HpaII) or a methylation-insensitive (MspI) restriction endonuclease. …

Isoform-Specific Effects Of Apoe On Neurite Outgrowth In Olfactory Epithelium Culture, Aseem Hussain, Minh Luong, Apryl Pooley, Britto P. Nathan

Britto P. Nathan

The apolipoprotein E4 (apoE4) genotype is a major risk factor for developing late-onset Alzheimer’s disease (AD). Inheritance of apoE4 is also associated with impairments in olfactory function in early stages of AD. In this project we examined the effects of the three common isoforms of human apoE (apoE2, apoE3, and apoE4) on neuronal differentiation and neurite outgrowth in explant cultures of mouse olfactory epithelium (OE).

An Acute Inflammatory Response In A Diabetic Alzheimer’S Disease Model, Krystal Courtney D. Belmonte, Jefferson Kinney

McNair Poster Presentations

Alzheimer’s disease (AD) is the most common form of dementia, accounting for 50 to 80 percent of all dementia cases. This neurodegenerative disease leads to neuronal death and tissue loss in the brain, resulting in the slow deterioration of memory, thinking skills, and eventually even the ability perform daily tasks. While it is not a normal part of aging, AD is mostly diagnosed in people over the age of 65; thus, the main risk factor for Alzheimer’s disease is increased age, though it is most likely other additional factors also contribute (Heese & Akatsu, 2006). Neuropathological hallmarks of AD include …

Isoform-Specific Effects Of Apoe On Neurite Outgrowth In Olfactory Epithelium Culture, Aseem Hussain, Minh Luong, Apryl Pooley, Britto P. Nathan

Faculty Research & Creative Activity

The apolipoprotein E4 (apoE4) genotype is a major risk factor for developing late-onset Alzheimer’s disease (AD). Inheritance of apoE4 is also associated with impairments in olfactory function in early stages of AD. In this project we examined the effects of the three common isoforms of human apoE (apoE2, apoE3, and apoE4) on neuronal differentiation and neurite outgrowth in explant cultures of mouse olfactory epithelium (OE).

Caspase-Cleaved Glial Fibrillary Acidic Protein Within Cerebellar White Matter Of The Alzheimer's Disease Brain, Troy T. Rohn, Lindsey W. Catlin, Wayne W. Poon

Biology Faculty Publications and Presentations

Although the cerebellum is generally thought of as an area spared of Alzheimer's disease (AD) pathology, recent evidence suggests that balance and mobility dysfunction may be magnified in affected individuals. In the present study, we sought to determine the degree of pathological changes within the cerebellum utilizing an antibody that specifically detects caspase-cleaved GFAP within degenerating astrocytes. Compared to control subjects, application of this antibody, termed the GFAP caspase-cleavage product (GFAPccp) antibody, revealed widespread labeling in cerebellar white matter with little staining observed in grey matter. Staining was observed within damaged astrocytes, was often localized near blood vessels and co-localized …

Isoform-Specific Effects Of Apoe On Neurite Outgrowth In Olfactory Epithelium Culture, Aseem Hussain, Minh Luong, Apryl Pooley, Britto Nathan

Faculty Research & Creative Activity

The apolipoprotein E4 (apoE4) genotype is a major risk factor for developing late-onset Alzheimer’s disease (AD). Inheritance of apoE4 is also associated with impairments in olfactory function in early stages of AD. In this project we examined the effects of the three common isoforms of human apoE (apoE2, apoE3, and apoE4) on neuronal differentiation and neurite outgrowth in explant cultures of mouse olfactory epithelium (OE).

Identification Of An Amino-Terminal Fragment Of Apolipoprotein E4 That Localizes To Neurofibrillary Tangles Of The Alzheimer’S Disease Brain, Troy T. Rohn, Lindsey W. Catlin, Kendra G. Coonse, Jeffrey W. Habig

Biology Faculty Publications and Presentations

Although the risk factor for harboring the apolipoprotein E4 (apoE4) allele in late-onset Alzheimer’s disease (AD) is well known, the mechanism by which apoE4 contributes to AD pathogenesis has yet to be clarified. Preferential cleavage of the ApoE4 isoform relative to other polymorphic forms appears to be significant, as the resulting fragments are associated with hallmarks of AD. To examine the possible role of apoE4 proteolysis in AD, we designed a site-directed antibody directed at position D172, which would yield a predicted amino-terminal fragment previously identified in AD brain extracts. Western blot analysis utilizing this novel antibody, termed the amino-terminal …

Depletion Of Beclin-1 Due To Proteolytic Cleavage By Caspases In The Alzheimer's Disease Brain, Troy T. Rohn, Ellen Wirawan, Raquel J. Brown, Jordan R. Harris, Eliezer Masliah, Peter Vandenabeele

Biology Faculty Publications and Presentations

The Beclin-1 protein is essential for the initiation of autophagy and recent studies suggest this function may be compromised in Alzheimer’s disease (AD). In addition, in vitro studies have supported a loss of function of Beclin-1 due to proteolytic modification by caspases. In the present study we examined whether caspase-cleavage of Beclin-1 occurs in the AD brain by designing a site-directed caspase-cleavage antibody based upon a known cleavage site within the protein at position D149. We confirmed that Beclin-1 is an excellent substrate for caspase-3 and demonstrate cleavage led to the formation of a 35 kDa C-terminal fragment labeled by …

Inhibition Of Aβ42 Aggregation Using Peptides Selected From Combinatorial Libraries, Michael Baine, Daniel S. Georgie, Elelta Z. Shiferraw, Theresa P. T. Nguyen, Luiza A. Nogaj, David A. Moffet

Chemistry and Biochemistry Faculty Works

Increasing evidence suggests that the aggregation of the small peptide Aβ42 plays an important role in the development of Alzheimer’s disease. Inhibiting the initial aggregation of Aβ42 may be an effective treatment for preventing, or slowing, the onset of the disease. Using an in vivo screen based on the enzyme EGFP, we have searched through two combinatorially diverse peptide libraries to identify peptides capable of inhibiting Aβ42 aggregation. From this initial screen, three candidate peptides were selected and characterized. ThT studies indicated that the selected peptides were capable of inhibiting amyloid aggregation. Additional ThT studies showed that one of the …

The Effect Of Exercise On Alzheimer’S Disease, Benjamin Korman

The Science Journal of the Lander College of Arts and Sciences

Alzheimer’s disease (AD) is a progressive neurodegenerative disease, from which there is no recovery. It begins with impaired memory and judgement and progresses to the point where those affected can no longer care themselves. Although the cause of AD is unknown, two significant abnormalities occur in the brain of its victims: neurofibrillary tangles and amyloid plaques. It has been well established that exercise improves mood and general well-being, however this paper will focus on the effect of exercise on AD. It will show that exercise can improve physical functioning of an individual with AD, however more importantly it will focus …

Caspase-Cleaved Tar Dna Binding Protein-43 Is A Major Pathological Finding In Alzheimer’S Disease, Troy T. Rohn

Biology Faculty Publications and Presentations

The TAR DNA binding protein-43 (TDP-43) has been identified as a major constituent of inclusions found in frontotemporal dementia with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). To determine a possible role for TDP-43 in Alzheimer’s disease (AD), a site-directed caspase-cleavage antibody to TDP-43 based upon a known caspase-3 cleavage consensus site within TDP-43 at position D219 was designed. In vitro, this antibody labeled the predicted 25 kDa caspase-cleavage fragment of TDP-43 without labeling full-length TDP-43 following digestion of recombinant TDP-43 with caspase-3 or treatment of Hela cells with staurosporine. Application of this antibody in postmortem brain sections …