Alzheimer's disease alters astrocytic functions related to neuronal support and transcellular internalization of mitochondria

Under physiological conditions in vivo astrocytes internalize and degrade neuronal mitochondria in a process called transmitophagy. Mitophagy is widely reported to be impaired in neurodegeneration but it is unknown whether and how transmitophagy is altered in Alzheimer's disease (AD). Here we report that the internalization and degradation of neuronal mitochondria are significantly increased in astrocytes isolated from aged AD mouse brains. We also demonstrate for the first time a similar phenomenon between human neurons and AD astrocytes, and in murine hippocampi in vivo. The results suggest the involvement of S100a4 in impaired mitochondrial transfer between neurons and aged AD astrocytes. Significant increases in the mitophagy regulator Ambra1 were observed in the aged AD astrocytes. These findings demonstrate altered neuron-supporting functions of aged AD astrocytes and provide a starting point for studying the molecular mechanisms of transmitophagy in AD.

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Targeting PPARalpha in Alzheimer's Disease

Current Alzheimer Research ◽

10.2174/1567205014666170505094549 ◽

2018 ◽

Vol 15 (4) ◽

pp. 345-354 ◽

Cited By ~ 13

Author(s):

Barbara D'Orio ◽

Anna Fracassi ◽

Maria Paola Cerù ◽

Sandra Moreno

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Redox Homeostasis ◽

Antioxidant Response ◽

Peroxisome Proliferator ◽

Prevailing Paradigm

Background: The molecular mechanisms underlying Alzheimer's disease (AD) are yet to be fully elucidated. The so-called “amyloid cascade hypothesis” has long been the prevailing paradigm for causation of disease, and is today being revisited in relation to other pathogenic pathways, such as oxidative stress, neuroinflammation and energy dysmetabolism. The peroxisome proliferator-activated receptors (PPARs) are expressed in the central nervous system (CNS) and regulate many physiological processes, such as energy metabolism, neurotransmission, redox homeostasis, autophagy and cell cycle. Among the three isotypes (α, β/δ, γ), PPARγ role is the most extensively studied, while information on α and β/δ are still scanty. However, recent in vitro and in vivo evidence point to PPARα as a promising therapeutic target in AD. Conclusion: This review provides an update on this topic, focussing on the effects of natural or synthetic agonists in modulating pathogenetic mechanisms at AD onset and during its progression. Ligandactivated PPARα inihibits amyloidogenic pathway, Tau hyperphosphorylation and neuroinflammation. Concomitantly, the receptor elicits an enzymatic antioxidant response to oxidative stress, ameliorates glucose and lipid dysmetabolism, and stimulates autophagy.

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Genetic Modifiers of Tauopathy in Drosophila

Genetics ◽

10.1093/genetics/165.3.1233 ◽

2003 ◽

Vol 165 (3) ◽

pp. 1233-1242

Author(s):

Joshua M Shulman ◽

Mel B Feany

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Genetic Modifier ◽

Genetic Modifiers ◽

Protein Tau ◽

Major Class ◽

Drosophila Model ◽

Tau Kinases

Abstract In Alzheimer's disease and related disorders, the microtubule-associated protein Tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles. Mutations in the tau gene cause familial frontotemporal dementia. To investigate the molecular mechanisms responsible for Tau-induced neurodegeneration, we conducted a genetic modifier screen in a Drosophila model of tauopathy. Kinases and phosphatases comprised the major class of modifiers recovered, and several candidate Tau kinases were similarly shown to enhance Tau toxicity in vivo. Despite some clinical and pathological similarities among neurodegenerative disorders, a direct comparison of modifiers between different Drosophila disease models revealed that the genetic pathways controlling Tau and polyglutamine toxicity are largely distinct. Our results demonstrate that kinases and phosphatases control Tau-induced neurodegeneration and have important implications for the development of therapies in Alzheimer's disease and related disorders.

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Formation of Toxic Amyloid Fibrils by Amyloidβ-Protein on Ganglioside Clusters

International Journal of Alzheimer s Disease ◽

10.4061/2011/956104 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

Katsumi Matsuzaki

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Physicochemical Properties ◽

Lipid Rafts ◽

Molecular Mechanisms ◽

Amyloid Fibrils ◽

Protein A ◽

Pivotal Role ◽

Membrane Interaction

It is widely accepted that the conversion of the soluble, nontoxic amyloidβ-protein (Aβ) monomer to aggregated toxic Aβrich inβ-sheet structures is central to the development of Alzheimer’s disease. However, the mechanism of the abnormal aggregation of Aβin vivo is not well understood. Accumulating evidence suggests that lipid rafts (microdomains) in membranes mainly composed of sphingolipids (gangliosides and sphingomyelin) and cholesterol play a pivotal role in this process. This paper summarizes the molecular mechanisms by which Aβaggregates on membranes containing ganglioside clusters, forming amyloid fibrils. Notably, the toxicity and physicochemical properties of the fibrils are different from those of Aβamyloids formed in solution. Furthermore, differences between Aβ-(1–40) and Aβ-(1–42) in membrane interaction and amyloidogenesis are also emphasized.

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Imaging and Molecular Mechanisms of Alzheimer’s Disease: A Review

International Journal of Molecular Sciences ◽

10.3390/ijms19123702 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3702 ◽

Cited By ~ 12

Author(s):

Grazia Femminella ◽

Tony Thayanandan ◽

Valeria Calsolaro ◽

Klara Komici ◽

Giuseppe Rengo ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Multimodal Imaging ◽

Molecular Mechanisms ◽

Imaging Techniques ◽

Structural Mri ◽

Imaging Biomarkers ◽

Significant Burden ◽

Made In

Alzheimer’s disease is the most common form of dementia and is a significant burden for affected patients, carers, and health systems. Great advances have been made in understanding its pathophysiology, to a point that we are moving from a purely clinical diagnosis to a biological one based on the use of biomarkers. Among those, imaging biomarkers are invaluable in Alzheimer’s, as they provide an in vivo window to the pathological processes occurring in Alzheimer’s brain. While some imaging techniques are still under evaluation in the research setting, some have reached widespread clinical use. In this review, we provide an overview of the most commonly used imaging biomarkers in Alzheimer’s disease, from molecular PET imaging to structural MRI, emphasising the concept that multimodal imaging would likely prove to be the optimal tool in the future of Alzheimer’s research and clinical practice.

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Monitoring phagocytic uptake of amyloid β into glial cell lysosomes in real time

10.1101/2020.03.29.002857 ◽

2020 ◽

Author(s):

Priya Prakash ◽

Krupal P. Jethava ◽

Nils Korte ◽

Pablo Izquierdo ◽

Emilia Favuzzi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Real Time ◽

Glial Cells ◽

Brain Slices ◽

Amyloid Β ◽

Disease Outcomes ◽

Underlying Mechanisms ◽

First Time

ABSTRACTPhagocytosis by glial cells is essential to regulate brain function during development and disease. Given recent interest in using amyloid β (Aβ)-targeted antibodies as a therapy for patients with Alzheimer’s disease, removal of Aβ by phagocytosis is likely protective early in Alzheimer’s disease, but remains poorly understood. Impaired phagocytic function of glial cells surrounding Aβ plaques during later stages in Alzheimer’s disease likely contributes to worsened disease outcomes, but the underlying mechanisms of how this occurs remain unknown. We have developed a human Aβ1-42 analogue (AβpH) that exhibits green fluorescence upon internalization into the acidic phagosomes of cells but is non-fluorescent at physiological pH. This allowed us to image, for the first time, glial uptake of AβpH in real time in live animals. Microglia phagocytose more AβpH than astrocytes in culture, in brain slices and in vivo. AβpH can be used to investigate the phagocytic mechanisms removing Aβ from the extracellular space, and thus could become a useful tool to study Aβ clearance at different stages of Alzheimer’s disease.

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Resveratrol and Neuroprotection: Impact and Its Therapeutic Potential in Alzheimer's Disease

Frontiers in Pharmacology ◽

10.3389/fphar.2020.619024 ◽

2020 ◽

Vol 11 ◽

Author(s):

Md. Habibur Rahman ◽

Rokeya Akter ◽

Tanima Bhattacharya ◽

Mohamed M. Abdel-Daim ◽

Saad Alkahtani ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Neuroprotective Effect ◽

Tau Proteins ◽

Amyloid Peptides ◽

Work Done

Alzheimer’s disease (AD) is a progressive cortex and hippocampal neurodegenerative disease which ultimately causes cognitively impaired decline in patients. The AD pathogen is a very complex process, including aggregation of Aβ (β-amyloid peptides), phosphorylation of tau-proteins, and chronic inflammation. Exactly, resveratrol, a polyphenol present in red wine, and many plants are indicated to show the neuroprotective effect on mechanisms mostly above. Resveratrol plays an important role in promotion of non-amyloidogenic cleavage of the amyloid precursor protein. It also enhances the clearance of amyloid beta-peptides and reduces the damage of neurons. Most experimental research on AD and resveratrol has been performed in many species, both in vitro and in vivo, during the last few years. Nevertheless, resveratrol’s effects are restricted by its bioavailability in the reservoir. Therefore, scientists have tried to improve its efficiency by using different methods. This review focuses on recent work done on the cell and animal cultures and also focuses on the neuroprotective molecular mechanisms of resveratrol. It also discusses about the therapeutic potential onto the treatment of AD.

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Nutrient signaling pathways regulate amyloid clearance and synaptic loss in Alzheimer’s disease

10.1101/2020.11.13.381186 ◽

2020 ◽

Author(s):

Mrityunjoy Mondal ◽

Jitin Bali ◽

Makis Tzioras ◽

Rosa C. Paolicelli ◽

Ali Jawaid ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Pathological State ◽

Amyloid Formation ◽

Synaptic Loss ◽

Synapse Loss ◽

Human Neurons ◽

Nutrient Signaling

SummaryExtra-cellular accumulation of Amyloid-β (Aβ) plaques is causatively associated with Alzheimer’s disease (AD). However, mechanisms that mediate the pre-pathological state of amyloid plaque formation remain elusive. Here, using paired RNAi and kinase inhibitor screens, we discovered that AKT-mediated insulin/nutrient signaling suppresses lysosomal clearance of Aβ and promotes amyloid formation. This mechanism is cell-autonomous and functions in multiple systems, including iPSC-derived human neurons and in vivo. Nutrient signaling regulates amyloid formation via distinct lysosomal functional mechanisms, while enhanced amino acid signaling promotes amyloid formation by transcriptionally suppressing lysosome biogenesis, and high intracellular cholesterol levels suppress lysosomal clearance of amyloid by increasing the number of non-functional lysosomes. The nutrient signaling pathway, present in both neurons and microglia, regulates lysosomal clearance of amyloid and microglia mediated synapse loss, both in vitro and in vivo. Clinically, older hyperlipidemic patients showed less synapse loss through microglia and performed better in cognitive tests. Thus, our results reveal a bi-partite cellular quality control system regulated by the insulinnutrient signaling that in neurons regulates Aβ peptide clearance and in microglia regulates synaptic loss, both processes causally associated with AD. Our results also caution against reducing amyloid through such processes as this might also result in synapse loss.

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NAD+ in Alzheimer’s Disease: Molecular Mechanisms and Systematic Therapeutic Evidence Obtained in vivo

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.668491 ◽

2021 ◽

Vol 9 ◽

Author(s):

Xinshi Wang ◽

Hai-Jun He ◽

Xi Xiong ◽

Shuoting Zhou ◽

Wen-Wen Wang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Stress Responses ◽

Molecular Mechanisms ◽

Functional Decline ◽

Atp Production ◽

Mitochondrial Homeostasis ◽

Preclinical Trials ◽

Cellular Bioenergetics

Mitochondria in neurons generate adenosine triphosphate (ATP) to provide the necessary energy required for constant activity. Nicotinamide adenine dinucleotide (NAD+) is a vital intermediate metabolite involved in cellular bioenergetics, ATP production, mitochondrial homeostasis, and adaptive stress responses. Exploration of the biological functions of NAD+ has been gaining momentum, providing many crucial insights into the pathophysiology of age-associated functional decline and diseases, such as Alzheimer’s disease (AD). Here, we systematically review the key roles of NAD+ precursors and related metabolites in AD models and show how NAD+ affects the pathological hallmarks of AD and the potential mechanisms of action. Advances in understanding the molecular roles of NAD+-based neuronal resilience will result in novel approaches for the treatment of AD and set the stage for determining whether the results of exciting preclinical trials can be translated into the clinic to improve AD patients’ phenotypes.

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Neurotrophin-3 Promotes the Neuronal Differentiation of BMSCs and Improves Cognitive Function in a Rat Model of Alzheimer's Disease

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.629356 ◽

2021 ◽

Vol 15 ◽

Author(s):

Zhongrui Yan ◽

Xianjing Shi ◽

Hui Wang ◽

Cuiping Si ◽

Qian Liu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Function ◽

Neuronal Differentiation ◽

Molecular Mechanisms ◽

Therapeutic Effects ◽

Model Of Alzheimer’S Disease ◽

Neurotrophin 3

Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) has the potential to be developed into an effective treatment for neurodegenerative diseases such as Alzheimer's disease (AD). However, the therapeutic effects of BMSCs are limited by their low neural differentiation rate. We transfected BMSCs with neurotrophin-3 (NT-3), a neurotrophic factor that promotes neuronal differentiation, and investigated the effects of NT-3 gene overexpression on the differentiation of BMSCs into neurons in vitro and in vivo. We further studied the possible molecular mechanisms. We found that overexpression of NT-3 promoted the differentiation of BMSCs into neurons in vitro and in vivo and improved cognitive function in rats with experimental AD. By contrast, silencing NT-3 inhibited the differentiation of BMSCs and decreased cognitive function in rats with AD. The Wnt/β-catenin signaling pathway was involved in the mechanism by which NT-3 gene modification influenced the neuronal differentiation of BMSCs in vitro and in vivo. Our findings support the prospect of using NT-3-transduced BMSCs for the development of novel therapies for AD.

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Progressive memory circuit impairments along with Alzheimer’s disease neuropathology spread: evidence from in vivo neuroimaging

10.21203/rs.2.23012/v1 ◽

2020 ◽

Author(s):

Kaicheng Li ◽

Shuyue Wang ◽

Xiao Luo ◽

Qingze Zeng ◽

Yerfan Jiaerken ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Memory Circuit ◽

Group 4 ◽

Starting Point ◽

Group 3 ◽

Group 2 ◽

Diagnosis Criteria

Abstract Background Along with Alzheimer’s disease (AD) continuum, AD neuropathologies propagate trans-neuronally, causing the memory circuit disorganization and memory deficit. However, no evidence supports the hypothesis in vivo to date. Methods Based on biological diagnosis criteria, we divided subjects into 5 groups by setting the CSF cutoff point at 192 pg/ml for Aβ 1-42 (A) and 23 pg/ml for P-tau 181 (T): Group 0, cognitively normal (CN) with normal Aβ 1-42 and P-tau 181 (A−T−); Group 1, CN with A+T−; Group 2, CN with A+T+; Group 3, mild cognitive impairments (MCI) with A+T+; Group 4, AD with A+T+. We defined the memory circuit as the hippocampus (HP), cingulum-angular bundles (CAB), and precuneus cortex, respectively representing the starting point, core connecting fiber, and connected downstream cortex. Then we assessed the HP subfields volume, CAB diffusion metric (whole tract-level and waypoint-wise), and precuneus volume. Finally, we correlated neuroimaging measures with cognitive and neuropathological data. Results Along AD continuum, HP subfields volume initially increased and then decreased, starting from the early stage (CN with A+T-). CAB integrity loss on both whole tract-level and waypoint-wise in MCI and AD with A+T+ and progressed along AD continuum. Regarding precuneus, we only found the decreased volume in MCI and AD with A+T+, with CN stage spared. Further, memory circuit structure impairment correlated with more AD neuropathology and worse memory profile. Conclusion Our results support the tau propagation theory in the memory circuit, suggested that the memory circuit impairments starting from the HP, then propagating to the downstream projection tract and cortex.

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