Neurodegeneration and convergent factors contributing to the deterioration of the cytoskeleton in Alzheimer's disease, cerebral ischemia and multiple sclerosis (Review)

Gutiérrez‐Vargas, Johanna; Castro-Álvarez, John Fredy; Berruecos, José Fernando Zapata; Abdul‐Rahim, Komal; Arteaga‐Noriega, Anibal

doi:10.3892/br.2022.1510

Cited by 15 publications

(7 citation statements)

References 110 publications

(124 reference statements)

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“…This observation was consistent with a dramatic reduction of fibroblast-like cells in the LMD pia enumerated using scRNAseq (66% of all cells in healthy pia versus 3% of all cells in LMD, Supplemental Figure 10B ). Previously, neurological degeneration was associated with a loss of cortical microtubule-associated protein 2 (MAP2) reactivity and gliosis marked by an increase in GFAP expression in schizophrenia, Parkinson’s disease, Alzheimer’s disease, and other neurodegenerative processes 71,72 . We also observed a loss of MAP2 reactivity in the cortex of animals with LMD ( Figure 6F ).…”

Section: Resultsmentioning

confidence: 99%

Branched-chain keto acids promote an immune-suppressive and neurodegenerative microenvironment in leptomeningeal disease

Khaled,

Ren,

Kundalia

et al. 2023

Preprint

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Leptomeningeal disease (LMD) occurs when tumors seed into the leptomeningeal space and cerebrospinal fluid (CSF), leading to severe neurological deterioration and poor survival outcomes. We utilized comprehensive multi-omics analyses of CSF from patients with lymphoma LMD to demonstrate an immunosuppressive cellular microenvironment and identified dysregulations in proteins and lipids indicating neurodegenerative processes. Strikingly, we found a significant accumulation of toxic branched-chain keto acids (BCKA) in the CSF of patients with LMD. The BCKA accumulation was found to be a pan-cancer occurrence, evident in lymphoma, breast cancer, and melanoma LMD patients. Functionally, BCKA disrupted the viability and function of endogenous T lymphocytes, chimeric antigen receptor (CAR) T cells, neurons, and meningeal cells. Treatment of LMD mice with BCKA-reducing sodium phenylbutyrate significantly improved neurological function, survival outcomes, and efficacy of anti-CD19 CAR T cell therapy. This is the first report of BCKA accumulation in LMD and provides preclinical evidence that targeting these toxic metabolites improves outcomes.

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Section: Resultsmentioning

confidence: 99%

Branched-chain keto acids promote an immune-suppressive and neurodegenerative microenvironment in leptomeningeal disease

Khaled,

Ren,

Kundalia

et al. 2023

Preprint

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“…Likewise, β-Tubulin III staining allowed us to observe other relevant neurodegenerative processes such as disorganization in the layers of the brain cortex, the presence of cortical dark neurons, and alterations in cortical and hippocampal neural processes and length of neuronal prolongations, as a consequence of impairments in the neuronal cytoskeleton. The cytoskeleton is the main intracellular structure that determines the morphology of neurons and maintains their integrity and, thus, disruption of its structure and function may underlie several neurodegenerative processes [ 28 ]. Therefore, we confirmed an age-related state of neurodegeneration in our animal model of ageing, as had already observed in previous studies [ 11 , 12 , 13 , 18 , 19 , 20 , 27 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

Chronic Treatment with Melatonin Improves Hippocampal Neurogenesis in the Aged Brain and Under Neurodegeneration

et al. 2022

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Adult hippocampal neurogenesis is altered during aging and under different neuropsychiatric and neurodegenerative diseases. Melatonin shows neurogenic and neuroprotective properties during aging and neuropathological conditions. In this study, we evaluated the effects of chronic treatment with melatonin on different markers of neurodegeneration and hippocampal neurogenesis using immunohistochemistry in the aged and neurodegenerative brains of SAMP8 mice, which is an animal model of accelerated senescence that mimics aging-related Alzheimer’s pathology. Neurodegenerative processes observed in the brains of aged SAMP8 mice at 10 months of age include the presence of damaged neurons, disorganization in the layers of the brain cortex, alterations in neural processes and the length of neuronal prolongations and β-amyloid accumulation in the cortex and hippocampus. This neurodegeneration may be associated with neurogenic responses in the hippocampal dentate gyrus of these mice, since we observed a neurogenic niche of neural stem and progenitor/precursors cells in the hippocampus of SAMP8 mice. However, hippocampal neurogenesis seems to be compromised due to alterations in the cell survival, migration and/or neuronal maturation of neural precursor cells due to the neurodegeneration levels in these mice. Chronic treatment with melatonin for 9 months decreased these neurodegenerative processes and the neurodegeneration-induced neurogenic response. Noticeably, melatonin also induced recovery in the functionality of adult hippocampal neurogenesis in aged SAMP8 mice.

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“…[71][72][73][74][75][76][77] Regulators of the cytoskeleton such as cofilin, RhoA/ROCK pathway components, MAPs, GSK3β have emerged as potential therapeutic targets for treating this dysregulation. 74,[77][78][79][80][81] It has previously been shown that F-actin levels are reduced in SCA1 and SCA3 model class IV da neurons. 35 Our results suggest that this reduction can be ameliorated by activating dendrite regeneration mechanisms via single branch injury.…”

Section: The Cytoskeleton In Regeneration and Neurodegenerative Diseasementioning

confidence: 99%

Dendrite injury, but not axon injury, triggers neuroprotection in Drosophila models of neurodegenerative disease

Prange,

Bhakta,

Sysoeva

et al. 2024

Preprint

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Dendrite defects and loss are early cellular alterations observed across neurodegenerative diseases that play a role in early disease pathogenesis. Dendrite degeneration can be modeled by expressing pathogenic polyglutamine disease transgenes in Drosophila neurons in vivo. Here, we show that we can protect against dendrite loss in neurons modeling neurodegenerative polyglutamine diseases through injury to a single primary dendrite branch. We find that this neuroprotection is specific to injury-induced activation of dendrite regeneration: neither injury to the axon nor injury just to surrounding tissues induces this response. We show that the mechanism of this regenerative response is stabilization of the actin (but not microtubule) cytoskeleton. We also demonstrate that this regenerative response may extend to other neurodegenerative diseases. Together, we provide evidence that activating dendrite regeneration pathways has the potential to slow or even reverse dendrite loss in neurodegenerative disease.

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Neurodegeneration and convergent factors contributing to the deterioration of the cytoskeleton in Alzheimer's disease, cerebral ischemia and multiple sclerosis (Review)

Cited by 15 publications

References 110 publications

Branched-chain keto acids promote an immune-suppressive and neurodegenerative microenvironment in leptomeningeal disease

Branched-chain keto acids promote an immune-suppressive and neurodegenerative microenvironment in leptomeningeal disease

Chronic Treatment with Melatonin Improves Hippocampal Neurogenesis in the Aged Brain and Under Neurodegeneration

Dendrite injury, but not axon injury, triggers neuroprotection in Drosophila models of neurodegenerative disease

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