Browsing by Subject "Neurodegeneration"
Now showing 1 - 10 of 80
Results Per Page
Sort Options
Item The 5th International Lafora Epilepsy Workshop: Basic science elucidating therapeutic options and preparing for therapies in the clinic(Elsevier, 2020-02) Gentry, Matthew S.; Afawi, Zaid; Armstrong, Dustin D.; Delgado-Escueta, Antonio; Goldberg, Y. Paul; Grossman, Tamar R.; Guinovart, Joan J.; Harris, Frank; Hurley, Thomas D.; Michelucci, Roberto; Minassian, Berge A.; Sanz, Pascual; Worby, Carolyn A.; Serratosa, Jose M.; Biochemistry and Molecular Biology, School of MedicineLafora disease (LD) is both a fatal childhood epilepsy and a glycogen storage disease caused by recessive mutations in either the Epilepsy progressive myoclonus 2A (EPM2A) or EPM2B genes. Hallmarks of LD are aberrant, cytoplasmic carbohydrate aggregates called Lafora bodies (LBs) that are a disease driver. The 5th International Lafora Epilepsy Workshop was recently held in Alcala de Henares, Spain. The workshop brought together nearly 100 clinicians, academic and industry scientists, trainees, National Institutes of Health (NIH) representation, and friends and family members of patients with LD. The workshop covered aspects of LD ranging from defining basic scientific mechanisms to elucidating a LD therapy or cure and a recently launched LD natural history study.Item A human induced pluripotent stem cell model of Alzheimer’s Disease‐associated fractalkine receptor polymorphism to assess AD‐related microglial dysfunction(Wiley, 2025-01-03) Tutrow, Kaylee; Harkin, Jade; Hernandez, Melody; Huang, Kang-Chieh S.; Bissel, Stephanie J.; Puntambekar, Shweta S.; Lamb, Bruce T.; Meyer, Jason S.; Medical and Molecular Genetics, School of MedicineBackground: Dysfunctional microglial activity has recently been identified as a potential mechanism leading to accumulation of amyloid beta and pTau and subsequent neurodegeneration in Alzheimer’s Disease. The CX3CR1/fractalkine axis serves as a mechanism for bi‐directional communication between microglia and neurons, respectively, to promote a resting, anti‐inflammatory state in microglia. Previous studies have demonstrated that deficiency in CX3CR1 signaling leads microglia to a more pro‐inflammatory phenotype, phagocytic deficits, and increased susceptibility of neurons to cell death. Additionally, the CX3CR1‐V249I polymorphism was recently identified as a potential risk allele for Alzheimer’s Disease with worsened Braak staging in post‐mortem Alzheimer’s patients. However, the role of fractalkine dysfunction in human cells and the mechanisms by which microglia with the CX3CR1‐V249I SNP contribute to neurodegeneration remain unclear. Method: To address this shortcoming, we utilized human induced pluripotent stem cells and CRISPR/Cas9 gene editing technology to elucidate the effects of the CX3CR1‐V249I polymorphism on human microglia‐like cells (hMGLs) compared to an isogenic control cell line. Isogenic control cells alongside both heterozygous and homozygous CX3CR1 V249I cell lines were differentiated in parallel to yield enriched populations of hMGLs. Resulting hMGLs were then assessed for uptake of amyloid beta 1‐42 using flow cytometry, cell death in response to cytokine starvation, changes in proliferation, and finally alterations to migratory behavior using a microfluidic chamber. Result: We demonstrate the effective differentiation of hMGLS from both isogenic control and CX3CR1‐V249I backgrounds, which express characteristic microglial markers and are functionally phagocytic. Microglia bearing the homozygous CX3CR1‐V249I allele, but not heterozygous cells, demonstrated decreased uptake of amyloid beta in vitro compared to isogenic controls. Additionally, homozygous V249I microglia demonstrated increased stress‐induced cell death, as well as altered proliferation and decreased migratory capability. Conclusion: These findings suggest that the CX3CR1‐V249I polymorphism may cause a dysfunctional microglia phenotype that may contribute to neuronal dysfunction and death. Ongoing work will expand upon the transcriptome and secretome profile of CX3CR1‐V249I microglia and elucidate how this gene variant contributes to Alzheimer’s Disease‐related neurodegeneration.Item Abnormal iron homeostasis and neurodegeneration(Frontiers Media, 2013-07-30) Muhoberac, Barry B.; Vidal, Ruben; Chemistry and Chemical Biology, School of ScienceAbnormal iron metabolism is observed in many neurodegenerative diseases, however, only two have shown dysregulation of brain iron homeostasis as the primary cause of neurodegeneration. Herein, we review one of these - hereditary ferritinopathy (HF) or neuroferritinopathy, which is an autosomal dominant, adult onset degenerative disease caused by mutations in the ferritin light chain (FTL) gene. HF has a clinical phenotype characterized by a progressive movement disorder, behavioral disturbances, and cognitive impairment. The main pathologic findings are cystic cavitation of the basal ganglia, the presence of ferritin inclusion bodies (IBs), and substantial iron deposition. Mutant FTL subunits have altered sequence and length but assemble into soluble 24-mers that are ultrastructurally indistinguishable from those of the wild type. Crystallography shows substantial localized disruption of the normally tiny 4-fold pores between the ferritin subunits because of unraveling of the C-termini into multiple polypeptide conformations. This structural alteration causes attenuated net iron incorporation leading to cellular iron mishandling, ferritin aggregation, and oxidative damage at physiological concentrations of iron and ascorbate. A transgenic murine model parallels several features of HF, including a progressive neurological phenotype, ferritin IB formation, and misregulation of iron metabolism. These studies provide a working hypothesis for the pathogenesis of HF by implicating (1) a loss of normal ferritin function that triggers iron accumulation and overproduction of ferritin polypeptides, and (2) a gain of toxic function through radical production, ferritin aggregation, and oxidative stress. Importantly, the finding that ferritin aggregation can be reversed by iron chelators and oxidative damage can be inhibited by radical trapping may be used for clinical investigation. This work provides new insights into the role of abnormal iron metabolism in neurodegeneration.Item Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein(Society for Neuroscience, 2002-11) Allen, Bridget; Ingram, Esther; Takao, Masaki; Smith, Michael J.; Jakes, Ross; Virdee, Kanwar; Yoshida, Hirotaka; Holzer, Max; Craxton, Molly; Emson, Piers C.; Atzori, Cristiana; Migheli, Antonio; Crowther, R. Anthony; Ghetti, Bernardino; Spillantini, Maria Grazia; Goedert, Michel; Pathology and Laboratory Medicine, School of MedicineThe identification of mutations in the Tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has made it possible to express human tau protein with pathogenic mutations in transgenic animals. Here we report on the production and characterization of a line of mice transgenic for the 383 aa isoform of human tau with the P301S mutation. At 5-6 months of age, homozygous animals from this line developed a neurological phenotype dominated by a severe paraparesis. According to light microscopy, many nerve cells in brain and spinal cord were strongly immunoreactive for hyperphosphorylated tau. According to electron microscopy, abundant filaments made of hyperphosphorylated tau protein were present. The majority of filaments resembled the half-twisted ribbons described previously in cases of FTDP-17, with a minority of filaments resembling the paired helical filaments of Alzheimer's disease. Sarkosyl-insoluble tau from brains and spinal cords of transgenic mice ran as a hyperphosphorylated 64 kDa band, the same apparent molecular mass as that of the 383 aa tau isoform in the human tauopathies. Perchloric acid-soluble tau was also phosphorylated at many sites, with the notable exception of serine 214. In the spinal cord, neurodegeneration was present, as indicated by a 49% reduction in the number of motor neurons. No evidence for apoptosis was obtained, despite the extensive colocalization of hyperphosphorylated tau protein with activated MAP kinase family members. The latter may be involved in the hyperphosphorylation of tau.Item Aging, beta‐amyloid deposition, and brain functional connectivity decline(Wiley, 2025-01-09) Yi, Dahyun; Chumin, Evgeny J.; Byun, Min Soo; Cha, Woo-Jin; Ahn, Hyejin; Kim, Yu Kyeong; Kang, Koung Mi; Sohn, Chul-Ho; Risacher, Shannon L.; Sporns, Olaf; Nho, Kwangsik; Saykin, Andrew J.; Lee, Dong Young; KBASE; Radiology and Imaging Sciences, School of MedicineBackground: Changes in brain network organization are influenced by aging. Accumulation of amyloid‐beta (Aβ) and neurodegeneration in the neocortex are also expected to alter neuronal networks. Therefore, we examined the relationship between aging and brain functional connectivity (FC), as well as the effect of brain Aβ on this relationship. Method: Resting state functional MRI (rsfMRI) from 594 participants spanning age and diagnostic severity of AD from the Korean Brain Aging Study for the Early Diagnosis and Prediction of AD (KBASE) was preprocessed as previously described in studies conducted at the Indiana AD Research Center (Chumin 2021, 2023). Cortical FC data from 200 regions (Schaefer 2018) grouped into 7 canonical resting state networks (RSN; Yeo 2011) was used to compute a network segregation measure (ratio of within‐ to between‐network connectivity (Chan 2014); here used as an index of FC) across all RSNs. Additionally, a subsample of older participants was classified as Aβ positive or negative based on global amyloid in Centiloid units (Klunk 2015). Result: Intrinsic network connectivity was reduced with increasing age beginning in young adulthood (Fig, left), resulting in a dedifferentiated, or less segregated, network architecture (t = ‐4.79, p = 0.000002). The relationship between age and network segregation was significant in the Aβ negative group (t = ‐4.09, p = 0.00005); however, such relationship was not found in the Aβ positive group (Fig, right). Fitted Aβ values were significantly different (Welch Two Sample t‐test: p < 2.2e‐16). Conclusion: This preliminary study elucidates age‐related decline of brain FC, quantified as network segregation, from young adulthood to late‐life, wherein RSN communication become less coherent, manifesting as a degeneration of FC structure. Such age‐related reduction pattern of brain connectivity appears disappear under the presence of pathological Aβ deposition in brain.Item Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer's disease(National Academy of Sciences, 2017-12-05) Rasmussen, Jay; Mahler, Jasmin; Beschorner, Natalie; Kaeser, Stephan A.; Häsler, Lisa M.; Baumann, Frank; Nyström, Sofie; Portelius, Erik; Blennow, Kaj; Lashley, Tammaryn; Fox, Nick C.; Sepulveda-Falla, Diego; Glatzel, Markus; Oblak, Adrian L.; Ghetti, Bernardino; Nilsson, K. Peter R.; Hammarström, Per; Staufenbiel, Matthias; Walker, Lary C.; Jucker, Mathias; Pathology and Laboratory Medicine, School of MedicineThe molecular architecture of amyloids formed in vivo can be interrogated using luminescent conjugated oligothiophenes (LCOs), a unique class of amyloid dyes. When bound to amyloid, LCOs yield fluorescence emission spectra that reflect the 3D structure of the protein aggregates. Given that synthetic amyloid-β peptide (Aβ) has been shown to adopt distinct structural conformations with different biological activities, we asked whether Aβ can assume structurally and functionally distinct conformations within the brain. To this end, we analyzed the LCO-stained cores of β-amyloid plaques in postmortem tissue sections from frontal, temporal, and occipital neocortices in 40 cases of familial Alzheimer's disease (AD) or sporadic (idiopathic) AD (sAD). The spectral attributes of LCO-bound plaques varied markedly in the brain, but the mean spectral properties of the amyloid cores were generally similar in all three cortical regions of individual patients. Remarkably, the LCO amyloid spectra differed significantly among some of the familial and sAD subtypes, and between typical patients with sAD and those with posterior cortical atrophy AD. Neither the amount of Aβ nor its protease resistance correlated with LCO spectral properties. LCO spectral amyloid phenotypes could be partially conveyed to Aβ plaques induced by experimental transmission in a mouse model. These findings indicate that polymorphic Aβ-amyloid deposits within the brain cluster as clouds of conformational variants in different AD cases. Heterogeneity in the molecular architecture of pathogenic Aβ among individuals and in etiologically distinct subtypes of AD justifies further studies to assess putative links between Aβ conformation and clinical phenotype.Item Anxiety in late life depression is associated with poorer performance across multiple cognitive domains(Cambridge University Press, 2024) Kryza-Lacombe, Maria; Kassel, Michelle T.; Insel, Philip S.; Rhodes, Emma; Bickford, David; Burns, Emily; Butters, Meryl A.; Tosun, Duygu; Aisen, Paul; Raman, Rema; Saykin, Andrew J.; Toga, Arthur W.; Jack, Clifford R., Jr.; Weiner, Michael W.; Nelson, Craig; Radiology and Imaging Sciences, School of MedicineObjective: Anxiety is a common comorbid feature of late-life depression (LLD) and is associated with poorer global cognitive functioning independent of depression severity. However, little is known about whether comorbid anxiety is associated with a domain-specific pattern of cognitive dysfunction. We therefore examined group differences (LLD with and without comorbid anxiety) in cognitive functioning performance across multiple domains. Method: Older adults with major depressive disorder (N = 228, ages 65-91) were evaluated for anxiety and depression severity, and cognitive functioning (learning, memory, language, processing speed, executive functioning, working memory, and visuospatial functioning). Ordinary least squares regression adjusting for age, sex, education, and concurrent depression severity examined anxiety group differences in performance on tests of cognitive functioning. Results: Significant group differences emerged for confrontation naming and visuospatial functioning, as well as for verbal fluency, working memory, and inhibition with lower performance for LLD with comorbid anxiety compared to LLD only, controlling for depression severity. Conclusions: Performance patterns identified among older adults with LLD and comorbid anxiety resemble neuropsychological profiles typically seen in neurodegenerative diseases of aging. These findings have potential implications for etiological considerations in the interpretation of neuropsychological profiles.Item APOE4 Drives Impairment in Astrocyte-Neuron Coupling in Alzheimer's Disease and Works Through Mechanisms in Early Disease to Influence Pathology(2023-05) Brink, Danika Marie Tumbleson; Lamb, Bruce; Bissel, Stephanie; Herbert, Brittney-Shea; Landreth, Gary; Puntambekar, Shweta; Saykin, Andrew; Zhang, ChiAlzheimer’s disease (AD) is a neurodegenerative disorder resulting in progressive memory loss, brain atrophy, and eventual death. AD pathology is characterized by the accumulation of neurotoxic amyloid-beta (Aβ) plaques, synapse loss, neurofibrillary tangles (NFTs), and neurodegeneration. The APOE4 allele is associated with a 3-fold increased risk for AD and results in increased Aβ plaque deposition, reduced Aβ clearance, and reduced synaptic plasticity. Although APOE expression is upregulated in microglia in AD, APOE is expressed primarily by astrocytes in the CNS. It is not well understood how astrocytic APOE drives the mechanisms that result in worsened AD outcomes. Here, digital spatial profiling and bioinformatics data suggest that APOE4 causes transcriptional dysregulation in early AD and may disrupt neuronal processes via astrocytes. Whole transcriptome data from plaque and non-plaque regions in the cortices and hippocampus of 4- and 8-month-old AD model mice expressing humanized APOE4/4 or APOE3/3 (control) were analyzed. Transcriptional dysregulation was increased in APOE4/4 AD mice compared to that in APOE3/3 at 4 but not 8 months of age, suggesting that early dysregulation of APOE4-driven disease mechanisms may shape degenerative outcomes in late-stage AD. Additionally, APOE4/4 potentially functions via plaque-independent mechanisms to influence neuronal function in early AD before the onset of pathology. Single-nuclei RNA sequencing data were obtained from human post-mortem astrocytes and the bioinformatic analyses revealed a novel astrocyte subtype that highly expresses several top genes involved in functional alterations associated with APOE4, including neuronal generation, development, and differentiation, and synaptic transmission and organization. Overall, our findings indicate that APOE4 may drive degenerative outcomes through the presented astrocyte candidate pathways. These pathways represent potential targets for investigations into early intervention strategies for APOE4/4 patients.Item Association of Brain Volume and Retinal Thickness in the Early Stages of Alzheimer’s Disease(IOS Press, 2023) Mathew, Sunu; WuDunn, Darrell; Mackay, Devin D.; Vosmeier, Aaron; Tallman, Eileen F.; Deardorff, Rachael; Harris, Alon; Farlow, Martin R.; Brosch, Jared R.; Gao, Sujuan; Apostolova, Liana G.; Saykin, Andrew J.; Risacher, Shannon L.; Radiology and Imaging Sciences, School of MedicineBackground: The eye has been considered a 'window to the brain,' and several neurological diseases including neurodegenerative conditions like Alzheimer's disease (AD) also show changes in the retina. Objective: To investigate retinal nerve fiber layer (RNFL) thickness and its association with brain volume via magnetic resonance imaging (MRI) in older adults with subjective or objective cognitive decline. Methods: 75 participants underwent ophthalmological and neurological evaluation including optical coherence tomography and MRI (28 cognitively normal subjects, 26 with subjective cognitive decline, 17 patients diagnosed with mild cognitive impairment, and 4 with AD). Differences in demographics, thickness of RNFL, and brain volume were assessed using ANCOVA, while partial Pearson correlations, covaried for age and sex, were used to compare thickness of the peripapillary RNFL with brain volumes, with p < 0.05 considered statistically significant. Results: Mean RNFL thickness was significantly correlated with brain volumes, including global volume (right eye r = 0.235 p = 0.046, left eye r = 0.244, p = 0.037), temporal lobe (right eye r = 0.242 p = 0.039, left eye r = 0.290, p = 0.013), hippocampal (right eye r = 0.320 p = 0.005, left eye r = 0.306, p = 0.008), amygdala (left eye r = 0.332, p = 0.004), and occipital lobe (right eye r = 0.264 p = 0.024) volumes. Conclusion: RNFL thickness in both eyes was positively associated with brain volumes in subjects with subjective and objective cognitive decline. The RNFL, however, did not correlate with the disease, but the small sample number makes it important to conduct larger studies. RNFL thickness may be a useful non-invasive and inexpensive tool for detection of brain neurodegeneration and may assist with diagnosis and monitoring of progression and treatment in AD.Item Astrocytes modulate neurodegenerative phenotypes associated with glaucoma in OPTN(E50K) human stem cell-derived retinal ganglion cells(Elsevier, 2022) Gomes, Cátia; VanderWall, Kirstin B.; Pan, Yanling; Lu, Xiaoyu; Lavekar, Sailee S.; Huang, Kang-Chieh; Fligor, Clarisse M.; Harkin, Jade; Zhang, Chi; Cummins, Theodore R.; Meyer, Jason S.; Medical and Molecular Genetics, School of MedicineAlthough the degeneration of retinal ganglion cells (RGCs) is a primary characteristic of glaucoma, astrocytes also contribute to their neurodegeneration in disease states. Although studies often explore cell-autonomous aspects of RGC neurodegeneration, a more comprehensive model of glaucoma should take into consideration interactions between astrocytes and RGCs. To explore this concept, RGCs and astrocytes were differentiated from human pluripotent stem cells (hPSCs) with a glaucoma-associated OPTN(E50K) mutation along with corresponding isogenic controls. Initial results indicated significant changes in OPTN(E50K) astrocytes, including evidence of autophagy dysfunction. Subsequently, co-culture experiments demonstrated that OPTN(E50K) astrocytes led to neurodegenerative properties in otherwise healthy RGCs, while healthy astrocytes rescued some neurodegenerative features in OPTN(E50K) RGCs. These results are the first to identify disease phenotypes in OPTN(E50K) astrocytes, including how their modulation of RGCs is affected. Moreover, these results support the concept that astrocytes could offer a promising target for therapeutic intervention in glaucoma.