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Highly cited articles on neurodegenerative diseases in 2021 (III)

Published on: 29 Dec 2021 Viewed: 317

Our staff editors continue to share exciting, interesting, and thought-provoking reading material in the recommended articles series.

This week, we would like to continue sharing several highly cited articles on neurodegenerative diseases in 2021.

Title: Alzheimer’s disease brain-derived extracellular vesicles spread tau pathology in interneurons
Authors: Zhi Ruan, Dhruba Pathak, Srinidhi Venkatesan Kalavai, Asuka Yoshii-Kitahara, Satoshi Muraoka, Nemil Bhatt, Kayo Takamatsu-Yukawa, Jianqiao Hu, Yuzhi Wang, Samuel Hersh, Maria Ericsson, Santhi Gorantla, Howard E Gendelman, Rakez Kayed, Seiko Ikezu, Jennifer I Luebke, Tsuneya Ikezu
Type: Original Article of Brain
Extracellular vesicles are highly transmissible and play critical roles in the propagation of tau pathology, although the underlying mechanism remains elusive. Here, for the first time, we comprehensively characterized the physicochemical structure and pathogenic function of human brain-derived extracellular vesicles isolated from Alzheimer’s disease, prodromal Alzheimer’s disease, and non-demented control cases. Alzheimer’s disease extracellular vesicles were significantly enriched in epitope-specific tau oligomers in comparison to prodromal Alzheimer’s disease or control extracellular vesicles as determined by dot blot and atomic force microscopy. Alzheimer’s disease extracellular vesicles were more efficiently internalized by murine cortical neurons, as well as more efficient in transferring and misfolding tau, than prodromal Alzheimer’s disease and control extracellular vesicles in vitro. Strikingly, the inoculation of Alzheimer’s disease or prodromal Alzheimer’s disease extracellular vesicles containing only 300 pg of tau into the outer molecular layer of the dentate gyrus of 18-month-old C57BL/6 mice resulted in the accumulation of abnormally phosphorylated tau throughout the hippocampus by 4.5 months, whereas inoculation of an equal amount of tau from control extracellular vesicles, isolated tau oligomers, or fibrils from the same Alzheimer’s disease donor showed little tau pathology. Furthermore, Alzheimer’s disease extracellular vesicles induced misfolding of endogenous tau in both oligomeric and sarkosyl-insoluble forms in the hippocampal region. Unexpectedly, phosphorylated tau was primarily accumulated in glutamic acid decarboxylase 67 (GAD67) GABAergic interneurons and, to a lesser extent, glutamate receptor 2/3-positive excitatory mossy cells, showing preferential extracellular vesicle-mediated GABAergic interneuronal tau propagation. Whole-cell patch clamp recordings of CA1 pyramidal cells showed significant reduction in the amplitude of spontaneous inhibitory post-synaptic currents. This was accompanied by reductions in c-fos+ GAD67+ neurons and GAD67+ neuronal puncta surrounding pyramidal neurons in the CA1 region, confirming reduced GABAergic transmission in this region. Our study posits a novel mechanism for the spread of tau in hippocampal GABAergic interneurons via brain-derived extracellular vesicles and their subsequent neuronal dysfunction.
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Title: Untangling the association of amyloid-β and tau with synaptic and axonal loss in Alzheimer’s disease
Authors: Joana B Pereira, Shorena Janelidze, Rik Ossenkoppele, Hlin Kvartsberg, Ann Brinkmalm, Niklas Mattsson-Carlgren, Erik Stomrud, Ruben Smith, Henrik Zetterberg, Kaj Blennow, Oskar Hansson
Type: Original Article of Brain
It is currently unclear how amyloid-β and tau deposition are linked to changes in synaptic function and axonal structure over the course of Alzheimer’s disease. Here, we assessed these relationships by measuring presynaptic (synaptosomal-associated protein 25, SNAP25; growth-associated protein 43, GAP43), postsynaptic (neurogranin, NRGN) and axonal (neurofilament light chain) markers in the CSF of individuals with varying levels of amyloid-β and tau pathology based on 18F-flutemetamol PET and 18F-flortaucipir PET. In addition, we explored the relationships between synaptic and axonal markers with cognition as well as functional and anatomical brain connectivity markers derived from resting-state functional MRI and diffusion tensor imaging. We found that the presynaptic and postsynaptic markers SNAP25, GAP43 and NRGN are elevated in early Alzheimer’s disease i.e. in amyloid-β-positive individuals without evidence of tau pathology. These markers were associated with greater amyloid-β pathology, worse memory and functional changes in the default mode network. In contrast, neurofilament light chain was abnormal in later disease stages, i.e. in individuals with both amyloid-β and tau pathology, and correlated with more tau and worse global cognition. Altogether, these findings support the hypothesis that amyloid-β and tau might have differential downstream effects on synaptic and axonal function in a stage-dependent manner, with amyloid-related synaptic changes occurring first, followed by tau-related axonal degeneration.
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Title: CNS glucose metabolism in Amyotrophic Lateral Sclerosis: a therapeutic target?
Authors: Tesfaye Wolde Tefera, Frederik J. Steyn, Shyuan T. Ngo, Karin Borges
Type: Review of <em >Cell & Bioscience
Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder primarily characterized by selective degeneration of both the upper motor neurons in the brain and lower motor neurons in the brain stem and the spinal cord. The exact mechanism for the selective death of neurons is unknown. A growing body of evidence demonstrates abnormalities in energy metabolism at the cellular and whole-body level in animal models and in people living with ALS. Many patients with ALS exhibit metabolic changes such as hypermetabolism and body weight loss. Despite these whole-body metabolic changes being observed in patients with ALS, the origin of metabolic dysregulation remains to be fully elucidated. A number of pre-clinical studies indicate that underlying bioenergetic impairments at the cellular level may contribute to metabolic dysfunctions in ALS. In particular, defects in CNS glucose transport and metabolism appear to lead to reduced mitochondrial energy generation and increased oxidative stress, which seem to contribute to disease progression in ALS. Here, we review the current knowledge and understanding regarding dysfunctions in CNS glucose metabolism in ALS focusing on metabolic impairments in glucose transport, glycolysis, pentose phosphate pathway, TCA cycle and oxidative phosphorylation. We also summarize disturbances found in glycogen metabolism and neuroglial metabolic interactions. Finally, we discuss options for future investigations into how metabolic impairments can be modified to slow disease progression in ALS. These investigations are imperative for understanding the underlying causes of metabolic dysfunction and subsequent neurodegeneration, and to also reveal new therapeutic strategies in ALS.
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Title: Increased LRRK2 kinase activity alters neuronal autophagy by disrupting the axonal transport of autophagosomes
Authors: C. Alexander Boecker, Juliet Goldsmith, Dan Dou, Gregory G. Cajka, Erika L. F. Holzbaur
Type: Article of Current Biology

  • Parkinson’s disease LRRK2-G2019S mutation disrupts axonal autophagosome transport
  • Rab29-induced LRRK2 hyperactivation also impairs autophagosome transport
  • Hyperactive LRRK2 recruits JIP4, causing a tug of war between autophagosome motors
  • Impaired axonal transport is accompanied by defective autophagosome acidification

Parkinson’s disease-causing mutations in the leucine-rich repeat kinase 2 (LRRK2) gene hyperactivate LRRK2 kinase activity and cause increased phosphorylation of Rab GTPases, important regulators of intracellular trafficking. We found that the most common LRRK2 mutation, LRRK2-G2019S, dramatically reduces the processivity of autophagosome transport in neurons in a kinase-dependent manner. This effect was consistent across an overexpression model, neurons from a G2019S knockin mouse, and human induced pluripotent stem cell (iPSC)-derived neurons gene edited to express the G2019S mutation, and the effect was reversed by genetic or pharmacological inhibition of LRRK2. Furthermore, LRRK2 hyperactivation induced by overexpression of Rab29, a known activator of LRRK2 kinase, disrupted autophagosome transport to a similar extent. Mechanistically, we found that hyperactive LRRK2 recruits the motor adaptor JNK-interacting protein 4 (JIP4) to the autophagosomal membrane, inducing abnormal activation of kinesin that we propose leads to an unproductive tug of war between anterograde and retrograde motors. Disruption of autophagosome transport correlated with a significant defect in autophagosome acidification, suggesting that the observed transport deficit impairs effective degradation of autophagosomal cargo in neurons. Our results robustly link increased LRRK2 kinase activity to defects in autophagosome transport and maturation, further implicating defective autophagy in the pathogenesis of Parkinson’s disease.
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Title: The pleiotropic neuroprotective effects of resveratrol in cognitive decline and Alzheimer’s disease pathology: From antioxidant to epigenetic therapy
Authors: Christian Griñán-Ferré, Aina Bellver-Sanchis, Vanessa Izquierdo, Rubén Corpas, Joan Roig-Soriano, Miguel Chillón, Cristina Andres-Lacueva, Milán Somogyvári, Csaba Sőti, Coral Sanfeliu, Mercè Pallàs
Type: Review of Ageing Research Reviews

  • Resveratrol exerts antioxidant, antinflammatory and maintains cellular proteostasis and mitochondrial function.
  • Resveratrol has been proposed as a beneficial compound to delay ageing and cellular senescence.
  • Epigenetic mechanisms can be modulated by oxidative stress and consequently resveratrol could modify epigenetic changes.
  • Intergenerational benefits induced by resveratrol are due to epigenetic modulation.

While the elderly segment of the population continues growing in importance, neurodegenerative diseases increase exponentially. Lifestyle factors such as nutrition, exercise, and education, among others, influence ageing progression, throughout life. Notably, the Central Nervous System (CNS) can benefit from nutritional strategies and dietary interventions that prevent signs of senescence, such as cognitive decline or neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. The dietary polyphenol Resveratrol (RV) possesses antioxidant and cytoprotective effects, producing neuroprotection in several organisms. The oxidative stress (OS) occurs because of Reactive oxygen species (ROS) accumulation that has been proposed to explain the cause of the ageing. One of the most harmful effects of ROS in the cell is DNA damage. Nevertheless, there is also evidence demonstrating that OS can produce other molecular changes such as mitochondrial dysfunction, inflammation, apoptosis, and epigenetic modifications, among others. Interestingly, the dietary polyphenol RV is a potent antioxidant and possesses pleiotropic actions, exerting its activity through various molecular pathways. In addition, recent evidence has shown that RV mediates epigenetic changes involved in ageing and the function of the CNS that persists across generations. Furthermore, it has been demonstrated that RV interacts with gut microbiota, showing modifications in bacterial composition associated with beneficial effects. In this review, we give a comprehensive overview of the main mechanisms of action of RV in different experimental models, including clinical trials and discuss how the interconnection of these molecular events could explain the neuroprotective effects induced by RV.
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