Medicine and Health Sciences Commons^™

Csf Protein Changes Associated With Hippocampal Sclerosis Risk Gene Variants Highlight Impact Of Grn/Pgrn, David W. Fardo, Yuriko Katsumata, John S. K. Kauwe, Yuetiva Deming, Oscar Harari, Carlos Cruchaga, Alzheimer’S Disease Neuroimaging Initiative, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

Objective—Hippocampal sclerosis of aging (HS-Aging) is a common cause of dementia in older adults. We tested the variability in cerebrospinal fluid (CSF) proteins associated with previously identified HS-Aging risk single nucleotide polymorphisms (SNPs).

Methods—Alzheimer’s Disease Neuroimaging Initiative cohort (ADNI; n=237) data, combining both multiplexed proteomics CSF and genotype data, were used to assess the association between CSF analytes and risk SNPs in four genes (SNPs): GRN (rs5848), TMEM106B (rs1990622), ABCC9 (rs704180), and KCNMB2 (rs9637454). For controls, non-HS-Aging SNPs in APOE (rs429358/rs7412) and MAPT (rs8070723) were also analyzed against Aβ1-42 and total tau CSF analytes.

Results—The GRN risk …

Genomics And Csf Analyses Implicate Thyroid Hormone In Hippocampal Sclerosis Of Aging, Peter T. Nelson, Yuriko Katsumata, Kwangsik Nho, Sergey C. Artiushin, Gregory A. Jicha, Wang-Xia Wang, Erin L. Abner, Andrew J. Saykin, Walter A. Kukull, Alzheimer’S Disease Neuroimaging Initiative (Adni), David W. Fardo

Sanders-Brown Center on Aging Faculty Publications

We report evidence of a novel pathogenetic mechanism in which thyroid hormone dysregulation contributes to dementia in elderly persons. Two single nucleotide polymorphisms (SNPs) on chromosome 12p12 were the initial foci of our study: rs704180 and rs73069071. These SNPs were identified by separate research groups as risk alleles for non-Alzheimer’s neurodegeneration. We found that the rs73069071 risk genotype was associated with hippocampal sclerosis (HS) pathology among people with the rs704180 risk genotype (National Alzheimer’s Coordinating Center/Alzheimer’s Disease Genetic Consortium data; n = 2113, including 241 autopsy-confirmed HS cases). Furthermore, both rs704180 and rs73069071 risk genotypes were associated with widespread brain …

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 …

Abcc9/Sur2 In The Brain: Implications For Hippocampal Sclerosis Of Aging And A Potential Therapeutic Target, Peter T. Nelson, Gregory A. Jicha, Wang-Xia Wang, Eseosa T. Ighodaro, Sergey C. Artiushin, Colin G. Nichols, David W. Fardo

Sanders-Brown Center on Aging Faculty Publications

The ABCC9 gene and its polypeptide product, SUR2, are increasingly implicated in human neurologic disease, including prevalent diseases of the aged brain. SUR2 proteins are a component of the ATP-sensitive potassium (“K _ATP ”) channel, a metabolic sensor for stress and/or hypoxia that has been shown to change in aging. The K _ATP channel also helps regulate the neurovascular unit. Most brain cell types express SUR2, including neurons, astrocytes, oligodendrocytes, microglia, vascular smooth muscle, pericytes, and endothelial cells. Thus it is not surprising that ABCC9 gene variants are associated with risk for human brain diseases. For example, Cantu syndrome is …

Novel Human Abcc9/Sur2 Brain-Expressed Transcripts And An Eqtl Relevant To Hippocampal Sclerosis Of Aging, Peter T. Nelson, Wang-Xia Wang, Bernard R. Wilfred, Angela Wei, James Dimayuga, Qingwei Huang, Eseosa T. Ighodaro, Sergey C. Artiushin, David W. Fardo

Sanders-Brown Center on Aging Faculty Publications

ABCC9 genetic polymorphisms are associated with increased risk for various human diseases including hippocampal sclerosis of aging. The main goals of this study were 1 > to detect the ABCC9 variants and define the specific 3′ untranslated region (3′UTR) for each variant in human brain, and 2 > to determine whether a polymorphism (rs704180) associated with risk for hippocampal sclerosis of aging pathology is also associated with variation in ABCC9 transcript expression and/or splicing. Rapid amplification of ABCC9 cDNA ends (3′RACE) provided evidence of novel 3′ UTR portions of ABCC9 in human brain. In silico and experimental studies were performed focusing on …

Mitochondria-Associated Micrornas In Rat Hippocampus Following Traumatic Brain Injury, Wang-Xia Wang, Nishant P. Visavadiya, Jignesh D. Pandya, Peter T. Nelson, Patrick G. Sullivan, Joe E. Springer

Sanders-Brown Center on Aging Faculty Publications

Traumatic brain injury (TBI) is a major cause of death and disability. However, the molecular events contributing to the pathogenesis are not well understood. Mitochondria serve as the powerhouse of cells, respond to cellular demands and stressors, and play an essential role in cell signaling, differentiation, and survival. There is clear evidence of compromised mitochondrial function following TBI; however, the underlying mechanisms and consequences are not clear. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression post-transcriptionally, and function as important mediators of neuronal development, synaptic plasticity, and neurodegeneration. Several miRNAs show altered expression following TBI; however, the …

Hippocampal Sclerosis Of Aging, A Prevalent And High-Morbidity Brain Disease, Peter T. Nelson, Charles D. Smith, Erin L. Abner, Bernard J. Wilfred, Wang-Xia Wang, Janna H. Neltner, Michael Baker, David W. Fardo, Richard J. Kryscio, Stephen W. Scheff, Gregory A. Jicha, Kurt A. Jellinger, Linda J. Van Eldik, Frederick A. Schmitt

Sanders-Brown Center on Aging Faculty Publications

Hippocampal sclerosis of aging (HS-Aging) is a causative factor in a large proportion of elderly dementia cases. The current definition of HS-Aging rests on pathologic criteria: neuronal loss and gliosis in the hippocampal formation that is out of proportion to AD-type pathology. HS-Aging is also strongly associated with TDP-43 pathology. HS-Aging pathology appears to be most prevalent in the oldest-old: autopsy series indicate that 5-30 % of nonagenarians have HS-Aging pathology. Among prior studies, differences in study design have contributed to the study-to-study variability in reported disease prevalence. The presence of HS-Aging pathology correlates with significant cognitive impairment which is …

A Study Of Small Rnas From Cerebral Neocortex Of Pathology-Verified Alzheimer's Disease, Dementia With Lewy Bodies, Hippocampal Sclerosis, Frontotemporal Lobar Dementia, And Non-Demented Human Controls, Sébastien S. Hébert, Wang-Xia Wang, Qi Zhu, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

MicroRNAs (miRNAs) are small (20-22 nucleotides) regulatory non-coding RNAs that strongly influence gene expression. Most prior studies addressing the role of miRNAs in neurodegenerative diseases (NDs) have focused on individual diseases such as Alzheimer's disease (AD), making disease-to-disease comparisons impossible. Using RNA deep sequencing, we sought to analyze in detail the small RNAs (including miRNAs) in the temporal neocortex gray matter from non-demented controls (n = 2), AD (n = 5), dementia with Lewy bodies (n = 4), hippocampal sclerosis of aging (n = 4), and frontotemporal lobar dementia (FTLD) (n = 5) cases, together accounting for the most prevalent …

Intracranial Injection Of Aav Expressing Nep But Not Ide Reduces Amyloid Pathology In App+Ps1 Transgenic Mice, Nikisha Carty, Kevin R. Nash, Milene Brownlow, Dana Cruite, Donna M. Wilcock, Maj-Linda B. Selenica, Daniel C. Lee, Marcia N. Gordon, Dave Morgan

Sanders-Brown Center on Aging Faculty Publications

The accumulation of β-amyloid peptides in the brain has been recognized as an essential factor in Alzheimer's disease pathology. Several proteases, including Neprilysin (NEP), endothelin converting enzyme (ECE), and insulin degrading enzyme (IDE), have been shown to cleave β-amyloid peptides (Aβ). We have previously reported reductions in amyloid in APP+PS1 mice with increased expression of ECE. In this study we compared the vector-induced increased expression of NEP and IDE. We used recombinant adeno-associated viral vectors expressing either native forms of NEP (NEP-n) or IDE (IDE-n), or engineered secreted forms of NEP (NEP-s) or IDE (IDE-s). In a six-week study, immunohistochemistry …

Early Stage Drug Treatment That Normalizes Proinflammatory Cytokine Production Attenuates Synaptic Dysfunction In A Mouse Model That Exhibits Age-Dependent Progression Of Alzheimer's Disease-Related Pathology, Adam D. Bachstetter, Christopher M. Norris, Pradoldej Sompol, Donna M. Wilcock, Danielle Goulding, Janna H. Neltner, Daret St. Clair, D. Martin Watterson, Linda J. Van Eldik

Sanders-Brown Center on Aging Faculty Publications

Overproduction of proinflammatory cytokines in the CNS has been implicated as a key contributor to pathophysiology progression in Alzheimer's disease (AD), and extensive studies with animal models have shown that selective suppression of excessive glial proinflammatory cytokines can improve neurologic outcomes. The prior art, therefore, raises the logical postulation that intervention with drugs targeting dysregulated glial proinflammatory cytokine production might be effective disease-modifying therapeutics if used in the appropriate biological time window. To test the hypothesis that early stage intervention with such drugs might be therapeutically beneficial, we examined the impact of intervention with MW01-2-151SRM (MW-151), an experimental therapeutic that …

Neuropathological Findings Processed By Artificial Neural Networks (Anns) Can Perfectly Distinguish Alzheimer's Patients From Controls In The Nun Study, Enzo Grossi, Massimo P. Buscema, David Snowdon, Piero Antuono

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Many reports have described that there are fewer differences in AD brain neuropathologic lesions between AD patients and control subjects aged 80 years and older, as compared with the considerable differences between younger persons with AD and controls. In fact some investigators have suggested that since neurofibrillary tangles (NFT) can be identified in the brains of non-demented elderly subjects they should be considered as a consequence of the aging process. At present, there are no universally accepted neuropathological criteria which can mathematically differentiate AD from healthy brain in the oldest old. The aim of this study is to discover …

Neuroprotective Action Of Cycloheximide Involves Induction Of Bcl-2 And Antioxidant Pathways, Katsutoshi Furukawa, Steven Estus, Weiming Fu, Robert J. Mark, Mark P. Mattson

Sanders-Brown Center on Aging Faculty Publications

The ability of the protein synthesis inhibitor cycloheximide (CHX) to prevent neuronal death in different paradigms has been interpreted to indicate that the cell death process requires synthesis of “killer” proteins. On the other hand, data indicate that neurotrophic factors protect neurons in the same death paradigms by inducing expression of neuroprotective gene products. We now provide evidence that in embryonic rat hippocampal cell cultures, CHX protects neurons against oxidative insults by a mechanism involving induction of neuroprotective gene products including the antiapoptotic gene bcl-2 and antioxidant enzymes. Neuronal survival after exposure to glutamate, FeSO₄, and amyloid β-peptide …