Stress-Induced Tau Phosphorylation: Functional Neuroplasticity or Neuronal Vulnerability?
Authors: Rissman, Robert A.
Article Type: Research Article
Abstract: Abnormally phosphorylated tau protein is a key component of the pathology seen in neurodegenerative tauopathies, such as Alzheimer's disease (AD). Despite its association with disease, tau phosphorylation (tau-P) also plays an important role in neuroplasticity, such as dendritic/synaptic remodeling seen in the hippocampus in response to environmental challenges, such as stress. To define the boundaries between neuroplasticity and neuropathology, studies have attempted to characterize the paradigms, stimuli, and signaling intermediates involved in stress-induced tau-P. Supporting an involvement of stress in AD are data demonstrating alterations in stress pathways and peptides in the AD brain and epidemiological data implicating stress exposure …as a risk factor for AD. In this review, the question of whether stress-induced tau-P can be used as a model for examining the relationship between functional neuroplasticity and neuronal vulnerability will be discussed. Show more
Keywords: Alzheimer's disease, corticotropin-releasing, hippocampus, hypothalamus, neurofibrillary tangles, phosphorylation, stress, tau
DOI: 10.3233/JAD-2009-1153
Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 453-457, 2009
Characterization of ATP Alternations in an Alzheimer's Disease Transgenic Mouse Model
Authors: Zhang, Cheng | Rissman, Robert A. | Feng, June
Article Type: Short Communication
Abstract: Mitochondrial impairment as evidenced by decline in adenosine 5′-triphosphate (ATP) is associated with oxidative stress in Alzheimer's disease neuropathology and suggests that mitochondria may fail to maintain cellular energy, through reduced ATP production in neurons. To gain insights into the ATP characteristics of Alzheimer's disease transgenic (Tg) mice, we investigated ATP contents in the brain and whole blood of Tg mice at three ages (1-, 5-, and 24-months old). Overall, our results demonstrate that tissue ATP contents in Tg mice are significantly reduced, suggesting a decrease of tissue ATP production and mitochondrial dysfunction.
Keywords: Adenosine 5′-triphosphate (ATP) contents, Alzheimer's disease, Alzheimer's disease transgenic mouse model, oxidative stress
DOI: 10.3233/JAD-141890
Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 375-378, 2015
Corticotropin-Releasing Factor Receptor-1 Antagonism Reduces Oxidative Damage in an Alzheimer's Disease Transgenic Mouse Model
Authors: Zhang, Cheng | Kuo, Ching-Chang | Moghadam, Setareh H. | Monte, Louise | Rice, Kenner C. | Rissman, Robert A.
Article Type: Research Article
Abstract: Reports from Alzheimer's disease (AD) biomarker work have shown a strong link between oxidative stress and AD neuropathology. The nonenzymatic antioxidant, glutathione (GSH), plays a crucial role in defense against reactive oxygen species and maintenance of GSH redox homeostasis. In particular, our previous studies on GSH redox imbalance have implicated oxidative stress induced by excessive reactive oxygen species as a major mediator of AD-like events, with the presence of S-glutathionylated proteins (Pr-SSG) appearing prior to overt AD neuropathology. Furthermore, evidence suggests that oxidative stress may be associated with dysfunction of the hypothalamic-pituitary-adrenal axis, leading to activation of inflammatory pathways and …increased production of corticotropin-releasing factor (CRF). Therefore, to investigate whether oxidative insults can be attenuated by reduction of central CRF signaling, we administered the type-1 CRF receptor (CRFR1) selective antagonist, R121919, to AD-transgenic mice beginning in the preclinical/prepathologic period (30-day-old) for 150 days, a timepoint where behavioral impairments and pathologic progression should be measureable. Our results indicate that R121919 treatment can significantly reduce Pr-SSG levels and increase glutathione peroxide activity, suggesting that interference of CRFR1 signaling may be useful as a preventative therapy for combating oxidative stress in AD. Show more
Keywords: Alzheimer's disease, corticotropin-releasing factor-1 receptor (CRFR1), glutathione, glutathione peroxide, glutathione reductase, oxidative stress, oxidized glutathione, R121919, S-glutathionylated protein
DOI: 10.3233/JAD-141722
Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 639-650, 2015
Growth Hormone-Releasing Hormone Modulation of Neuronal Exosome Biomarkers in Mild Cognitive Impairment
Authors: Winston, Charisse N. | Goetzl, Edward J. | Baker, Laura D. | Vitiello, Michael V. | Rissman, Robert A.
Article Type: Research Article
Abstract: Age-related changes in cognition are linked to decreased expression of somatotropins, GHRH and IGF-1. Mild cognitive impairment (MCI) and Alzheimer’s disease (AD) are heterogeneous conditions. The loss of GHRH signaling in the brain may be mechanistically involved in AD pathogenesis. The consequent need to identify AD at an early and perhaps more treatable stage has fueled research into blood-based, exosome biomarkers. Plasma exosomes from participants enrolled in a randomized, double-blind, placebo-controlled 20-week trial of GHRH administration, were isolated, precipitated, and enriched by immuno-absorption with anti-L1CAM antibody (neural adhesion protein) from adults with MCI and age-matched, cognitively normal controls (CNC). Extracted …protein cargo from neuronally-derived exosomes (NDEs) were assessed by ELISAs for protein levels implicated in AD neuropathology and for synaptic proteins altered by AD. Plasma NDE concentrations of Aβ1-42 were significantly increased while plasma NDE concentrations of NRGN, synaptophysin, synaptotagmin, and synaptopodin were significantly decreased in patients with MCI, independent of GHRH treatment. Plasma NDE concentrations of ptau-S396 and GAP43 were not affected by cognitive status (CNC versus MCI) or by GHRH treatment. Aβ1-42 , neurogranin (NRGN), synaptophysin, synaptotagmin, and synaptopodin demonstrated the highest diagnostic accuracy for distinguishing between CNC and MCI patients, while synaptophysin and synaptotagmin demonstrated moderate accuracy in distinguishing between placebo-treated and GHRH-treated, MCI patients. Show more
Keywords: Amyloid, biomarker, GHRH, growth hormone, mild cognitive impairment, neuronal exosomes, synapse, tau
DOI: 10.3233/JAD-180302
Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 971-981, 2018
Extracellular Vesicles Isolated from Familial Alzheimer’s Disease Neuronal Cultures Induce Aberrant Tau Phosphorylation in the Wild-Type Mouse Brain
Authors: Aulston, Brent | Liu, Qing | Mante, Michael | Florio, Jazmin | Rissman, Robert A. | Yuan, Shauna H.
Article Type: Research Article
Abstract: Extracellular vesicles (EVs) are a heterogeneous group of secreted particles consisting of microvesicles, which are released by budding of the cellular membrane, and exosomes, which are secreted through exocytosis from multivesicular bodies. EV cargo consists of a wide range of proteins and nucleic acids that can be transferred between cells. Importantly, EVs may be pathogenically involved in neurodegenerative diseases such as Alzheimer’s disease (AD). While EVs derived from AD neurons have been found to be neurotoxic in vitro , little is known about the pathological consequences of AD EVs in vivo . Furthermore, although all known familial AD (fAD) mutations …involve either amyloid-β protein precursor (AβPP) or the machinery that processes AβPP, hyperphosphorylation of the microtubule associated protein tau appears to play a critical role in fAD-associated neurodegeneration, and previous reports suggest EVs may propagate tau pathology in the AD brain. Therefore, we hypothesized that fAD EVs may have a mechanistic involvement in the development of fAD-associated tau pathology. To test this, we isolated EVs from iPSC-derived neuronal cultures generated from an fAD patient harboring a A246E mutation to presenilin-1 and stereotactically injected these EVs into the hippocampi of wild-type C57BL/6 mice. Five weeks after injection, mice were euthanized and pathology evaluated. Mice injected with fAD EVs displayed increased tau phosphorylation at multiple sites relative to PBS and non-disease control EV injected groups. Moreover, fAD EV injected hippocampi contained significantly more tau inclusions in the CA1 hippocampal neuronal field than controls. In total, these findings identify EVs as a potential mediator of fAD-associated tau dysregulation and warrant future studies to investigate the therapeutic potential of EV-targeted treatments for fAD. Show more
Keywords: Alzheimer’s disease, C57BL/6, extracellular vesicles, induced pluripotent stem cells, tau, tauopathy
DOI: 10.3233/JAD-190656
Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 575-585, 2019
A Precision Medicine Approach to Treating Alzheimer’s Disease Using Rosiglitazone Therapy: A Biomarker Analysis of the REFLECT Trials
Authors: O’Bryant, Sid E. | Zhang, Fan | Petersen, Melissa | Johnson, Leigh | Hall, James | Rissman, Robert A.
Article Type: Research Article
Abstract: Background: The REFLECT trials were conducted to examine the treatment of mild-to-moderate Alzheimer’s disease utilizing a peroxisome proliferator-activated receptor gamma agonist. Objective: To generate a predictive biomarker indicative of positive treatment response using samples from the previously conducted REFLECT trials. Methods: Data were analyzed on 360 participants spanning multiple negative REFLECT trials, which included treatment with rosiglitazone and rosiglitazone XR. Support vector machine analyses were conducted to generate a predictive biomarker profile. Results: A pre-defined 6-protein predictive biomarker (IL6, IL10, CRP, TNFα, FABP-3, and PPY) correctly classified treatment response with 100%accuracy across study arms for REFLECT Phase II trial (AVA100193) …and multiple Phase III trials (AVA105640, AV102672, and AVA102670). When the data was combined across all rosiglitazone trial arms, a global RSG-predictive biomarker with the same 6-protein predictive biomarker was able to accurately classify 98%of treatment responders. Conclusion: A predictive biomarker comprising of metabolic and inflammatory markers was highly accurate in identifying those patients most likely to experience positive treatment response across the REFLECT trials. This study provides additional proof-of-concept that a predictive biomarker can be utilized to help with screening and predicting treatment response, which holds tremendous benefit for clinical trials. Show more
Keywords: Alzheimer’s disease, clinical trial, predictive biomarker, rosiglitazone
DOI: 10.3233/JAD-201610
Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 557-568, 2021
Increased Tau Phosphorylation and Aggregation in the Hippocampus of Mice Overexpressing Corticotropin-Releasing Factor
Authors: Campbell, Shannon N. | Zhang, Cheng | Monte, Louise | Roe, Allyson D. | Rice, Kenner C. | Taché, Yvette | Masliah, Eliezer | Rissman, Robert A.
Article Type: Research Article
Abstract: Clinical and basic science research suggests that stress and/or changes in central stress signaling intermediates may be involved in Alzheimer's disease (AD) pathogenesis. Although the links between stress and AD remain unsettled, data from our group and others have established that stress exposure in rodents may confer susceptibility to AD pathology by inducing hippocampal tau phosphorylation (tau-P). Work in our laboratory has shown that stress-induced tau-P requires activation of the type-1 corticotropin-releasing factor receptor (CRFR1). CRF overexpressing (CRF-OE) mice are a model of chronic stress that display cognitive impairment at 9–10 month of age. In this study we used 6–7 …month old CRF-OE mice to examine whether sustained exposure to CRF and stress steroids would impact hippocampal tau-P and kinase activity in the presence or absence of the CRFR1-specific antagonist, R121919, given daily for 30 days. CRF-OE mice had significantly elevated tau-P compared to wild type (WT) mice at the AT8 (S202 /T204 ), PHF-1 (S396/404 ), S262 , and S422 sites. Treating CRF-OE mice with R121919 blocked phosphorylation at the AT8 (S202 /T204 ) and PHF-1 (S396/404 ) sites, but not at the S262 and S422 sites and reduced phosphorylation of c-Jun N Terminal Kinase (JNK). Examination of hippocampal extracts from CRF-OE mice at the ultrastructural level revealed negatively stained round/globular aggregates that were positively labeled by PHF-1. These data suggest critical roles for CRF and CRFR1 in tau-P and aggregation and may have implications for the development of AD cognitive decline. Show more
Keywords: Alzheimer's disease, corticotropin-releasing factor (CRF), corticotropin-releasing factor receptor (CRFR), electron microscopy, hippocampus, immunohistochemistry, stress, tau phosphorylation (tau-P), western blot
DOI: 10.3233/JAD-141281
Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 967-976, 2015
Plasma Neurofilament Light and Alzheimer’s Disease Biomarkers in Down Syndrome: Results from the Down Syndrome Biomarker Initiative (DSBI)
Authors: Rafii, Michael S. | Donohue, Michael C. | Matthews, Dawn C. | Muranevici, Gabriela | Ness, Seth | O’Bryant, Sid E. | Rissman, Robert A.
Article Type: Research Article
Abstract: Background: Adults with Down syndrome (DS) are at very high risk for Alzheimer’s disease (AD). Neurofilament light (NF-L) has emerged as a potential blood-based biomarker of neurodegeneration due to AD. Objective: To understand the relationship between plasma NF-L with age, brain amyloid, and tau pathology, neurodegeneration as well as cognitive and functional performance. Methods: We analyzed imaging data as well as cognitive measures in relation to plasma NF-L in adults with DS, ages 30 to 60 who were enrolled in the Down Syndrome Biomarker Initiative. Results: We found significant correlations between NF-L plasma concentrations and amyloid pathology (r = 0.73, p … = 0.007, pa = 0.041) and significant inverse correlations with regional glucose metabolism in 5 of 6 regions examined, which were Anterior cingulate (r = –0.55, p = 0.067, pa = 0.067), Posterior cingulate r = –0.90, p < 0.001, pa < 0.001), Lateral Temporal (r = –0.78, p = 0.004, pa = 0.012), Frontal cortex (r = –0.90, p < 0.001, p pa < 0.001), Parietal cortex (r = –0.82, p = 0.002, pa = 0.008), Precuneus (r = –0.73, pa = 0.010, pa = 0.020), and with hippocampal volume (r = –0.52, p = 0.084, pa = 0.084); and an inverse correlation with direct measures of cognition: CAMCOG (r = –0.66 p = 0.022, pa = 0.066) and positive correlation with CANTAB Paired Associates Learning (PAL) error rate (r = 0.68, p = 0.015, pa = 0.060). Finally, we found inverse relationships with informant-based functional measures (r = –0.57, p = 0.059, pa = 0.084) and OMQ-PF (r = –0.74, p = 0.008, pa = 0.041). Conclusion: Plasma NF-L is associated with progressive neurodegeneration as well as with declines in cognitive and functional measures in adults with DS. Show more
Keywords: Alzheimer’s disease, amyloid, biomarkers, blood, Down syndrome, neurofilament light, plasma, tau
DOI: 10.3233/JAD-190322
Citation: Journal of Alzheimer's Disease, vol. 70, no. 1, pp. 131-138, 2019
Hippocampal Reduction of α-Synuclein via RNA Interference Improves Neuropathology in Alzheimer’s Disease Mice
Authors: Leitão, André D.G. | Spencer, Brian | Sarsoza, Floyd | Ngolab, Jennifer | Amalraj, Jessica | Masliah, Eliezer | Wu, Chengbiao | Rissman, Robert A.
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) cases are often characterized by the pathological accumulation of α-synuclein (α-syn) in addition to amyloid-β (Aβ) and tau hallmarks. The role of α-syn has been extensively studied in synucleinopathy disorders, but less so in AD. Recent studies have shown that α-syn may also play a role in AD and its downregulation may be protective against the toxic effects of Aβ accumulation. Objective: We hypothesized that selectively knocking down α-syn via RNA interference improves the neuropathological and biochemical findings in AD mice. Methods: Here we used amyloid precursor protein transgenic (APP-Tg) mice to model AD and explore …pathologic and behavioral phenotypes with knockdown of α-syn using RNA interference. We selectively reduced α-syn levels by stereotaxic bilateral injection of either LV-shRNA α-syn or LV-shRNA-luc (control) into the hippocampus of AD mice. Results: We found that downregulation of α-syn results in significant reduction in the number of Aβ plaques. In addition, mice treated with LV-shRNA α-syn had amelioration of abnormal microglial activation (Iba1) and astrocytosis (GFAP) phenotypes in AD mice. Conclusion: Our data suggests a novel link between Aβ and α-syn pathology as well as a new therapeutic angle for targeting AD. Show more
Keywords: Alzheimer’s disease, alpha-synuclein, amyloid-β, biomarkers, lentivirus
DOI: 10.3233/JAD-230232
Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 349-361, 2023
Impact of CRFR1 Ablation on Amyloid-β Production and Accumulation in a Mouse Model of Alzheimer's Disease
Authors: Campbell, Shannon N. | Zhang, Cheng | Roe, Allyson D. | Lee, Nickey | Lao, Kathleen U. | Monte, Louise | Donohue, Michael C. | Rissman, Robert A.
Article Type: Research Article
Abstract: Stress exposure and the corticotropin-releasing factor (CRF) system have been implicated as mechanistically involved in both Alzheimer's disease (AD) and associated rodent models. In particular, the major stress receptor, CRF receptor type 1 (CRFR1), modulates cellular activity in many AD-relevant brain areas, and has been demonstrated to impact both tau phosphorylation and amyloid-β (Aβ) pathways. The overarching goal of our laboratory is to develop and characterize agents that impact the CRF signaling system as disease-modifying treatments for AD. In the present study, we developed a novel transgenic mouse to determine whether partial or complete ablation of CRFR1 was feasible in …an AD transgenic model and whether this type of treatment could impact Aβ pathology. Double transgenic AD mice (PSAPP) were crossed to mice null for CRFR1; resultant CRFR1 heterozygous (PSAPP-R1+/− ) and homozygous (PSAPP-R1−/− ) female offspring were used at 12 months of age to examine the impact of CRFR1 disruption on the severity of AD Aβ levels and pathology. We found that both PSAPP-R1+/− and PSAPP-R1−/− had significantly reduced Aβ burden in the hippocampus, insular, rhinal, and retrosplenial cortices. Accordingly, we observed dramatic reductions in Aβ peptides and AβPP-CTFs, providing support for a direct relationship between CRFR1 and Aβ production pathways. In summary, our results suggest that interference of CRFR1 in an AD model is tolerable and is efficacious in impacting Aβ neuropathology. Show more
Keywords: Alzheimer's disease, amyloid-β, corticotropin-releasing factor, corticotropin-releasing factor receptor 1, hippocampus, hypothalamic-pituitary adrenal axis, stress, triple transgenic
DOI: 10.3233/JAD-142844
Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1175-1184, 2015