scholarly journals Stabilization of dynamic microtubules by mDia1 drives Tau-dependent Aβ1–42 synaptotoxicity

2017 ◽  
Vol 216 (10) ◽  
pp. 3161-3178 ◽  
Author(s):  
Xiaoyi Qu ◽  
Feng Ning Yuan ◽  
Carlo Corona ◽  
Silvia Pasini ◽  
Maria Elena Pero ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Axonal Transport ◽  
Dendritic Spines ◽  
Posttranslational Modifications ◽  
Hippocampal Neurons ◽  
Neuronal Damage ◽  
Driving Factors ◽  
Hyperphosphorylated Tau ◽  
Tau Hyperphosphorylation

Oligomeric Amyloid β1–42 (Aβ) plays a crucial synaptotoxic role in Alzheimer’s disease, and hyperphosphorylated tau facilitates Aβ toxicity. The link between Aβ and tau, however, remains controversial. In this study, we find that in hippocampal neurons, Aβ acutely induces tubulin posttranslational modifications (PTMs) and stabilizes dynamic microtubules (MTs) by reducing their catastrophe frequency. Silencing or acute inhibition of the formin mDia1 suppresses these activities and corrects the synaptotoxicity and deficits of axonal transport induced by Aβ. We explored the mechanism of rescue and found that stabilization of dynamic MTs promotes tau-dependent loss of dendritic spines and tau hyperphosphorylation. Collectively, these results uncover a novel role for mDia1 in Aβ-mediated synaptotoxicity and demonstrate that inhibition of MT dynamics and accumulation of PTMs are driving factors for the induction of tau-mediated neuronal damage.

scholarly journals Programmed Cell Death Protein 1 Blockade Reduces Glycogen Synthase Kinase 3β Activity and Tau Hyperphosphorylation in Alzheimer’s Disease Mouse Models

2021 ◽  
Vol 9 ◽  
Author(s):  
Yulian Zou ◽  
Chen-Ling Gan ◽  
Zhiming Xin ◽  
Hai-Tao Zhang ◽  
Qi Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Mouse Models ◽  
Glycogen Synthase ◽  
Neuronal Damage ◽  
Amyloid Β ◽  
Glycogen Synthase Kinase ◽  
Tau Hyperphosphorylation

Alzheimer’s disease (AD) is a central nervous system degenerative disease, with no effective treatment to date. Administration of immune checkpoint inhibitors significantly reduces neuronal damage and tau hyperphosphorylation in AD, but the specific mechanism is unclear. Here, we found that programmed cell death-receptor 1 (PD1) and its ligand PDL1 were induced by an intracerebroventricular injection of amyloid-β; they were significantly upregulated in the brains of APP/PS1, 5×FAD mice and in SH-SY5Y-APP cell line compared with control. The PD1 and PDL1 levels positively correlated with the glycogen synthase kinase 3 beta (GSK3β) activity in various AD mouse models, and the PDL1-GSK3β immune complex was found in the brain. The application of PD1-blocking antibody reduced tau hyperphosphorylation and GSK3β activity and prevented memory impairments. Mechanistically, we identified PD1 as a critical regulator of GSK3β activity. These results suggest that the immune regulation of the PD1/PDL1 axis is closely involved in AD.

scholarly journals Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease

2020 ◽  
Vol 140 (6) ◽  
pp. 793-810
Author(s):  
Nils Korte ◽  
Ross Nortley ◽  
David Attwell
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Neuronal Damage ◽  
Hyperphosphorylated Tau ◽  
Therapeutic Approaches ◽  
Pathological Mechanism ◽  
Amyloid Cascade ◽  
Aβ Production

AbstractTherapies targeting late events in Alzheimer’s disease (AD), including aggregation of amyloid beta (Aβ) and hyperphosphorylated tau, have largely failed, probably because they are given after significant neuronal damage has occurred. Biomarkers suggest that the earliest event in AD is a decrease of cerebral blood flow (CBF). This is caused by constriction of capillaries by contractile pericytes, probably evoked by oligomeric Aβ. CBF is also reduced by neutrophil trapping in capillaries and clot formation, perhaps secondary to the capillary constriction. The fall in CBF potentiates neurodegeneration by upregulating the BACE1 enzyme that makes Aβ and by promoting tau hyperphosphorylation. Surprisingly, therefore, CBF reduction may play a crucial role in driving cognitive decline by initiating the amyloid cascade itself, or being caused by and amplifying Aβ production. Here, we review developments in this area that are neglected in current approaches to AD, with the aim of promoting novel mechanism-based therapeutic approaches.

scholarly journals Clinical and Biophysical Principles of Vascular Dementia and Alzheimer’s Disease Treatment

2019 ◽  
Vol 5 (5) ◽  
pp. 57-72 ◽  
Author(s):  
S. Bulgakova ◽  
P. Romanchuk ◽  
A. Volobuev
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Vascular Dementia ◽  
Hippocampal Neurons ◽  
Structural Changes ◽  
Neuronal Damage ◽  
Oxidant Stress ◽  
Cerebral Hypoperfusion ◽  
Term Care ◽  
Β Amyloid

Biophysics of blood circulation in Alzheimer’s disease is characterized by disorders of laminar blood flow and cerebral hypoperfusion. As a result, failure intracellular metabolism, there is a cascade of changes in neurons associated with the processes of excitotoxicity and oxidant stress, which in turn stimulates amyloidogenesis. Experimental and 25-year observations have shown that the long-existing state of hypoperfusion leads to hippocampal disorders. This process is accompanied by memory impairment, structural changes in the capillaries in the hippocampus, impaired glucose and protein metabolism, β–amyloid deposition, activation of glial tissue, death of hippocampal neurons. Neuroreflex disruption in the ‘cerebral heart’ and a violation of cerebrovascular homeostasis contributes to the development of vascular dementia through the following mechanisms, including cerebral microangiopathy, endothelial dysfunction, oxidative stress, neuronal damage, the increase in β–amyloid neurotoxicity, apoptosis, etc. The duration of therapy with antiglutamatergic and multimodal drugs in Alzheimer’s disease requires constant multidisciplinary monitoring of targets and medical and social control in the system of long-term care. Lifelong acquisition of knowledge, information positive Nano communication enable the preservation of mental health and active longevity. Innovative methods of P4-medicine of neuroplasticity management allow to carry out timely prevention of the factors reducing neuroplasticity, to keep factors of positive influence on visceral and cognitive brain, and the main thing — in due time to apply in practical health care the combined methods of preservation and development of the human cognitive brain.

scholarly journals Ganoderma lucidum Triterpenoids (GLTs) Reduce Neuronal Apoptosis via Inhibition of ROCK Signal Pathway in APP/PS1 Transgenic Alzheimer’s Disease Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Nanhui Yu ◽  
Yongpan Huang ◽  
Yu Jiang ◽  
Lianhong Zou ◽  
Xiehong Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Signaling Pathway ◽  
Ganoderma Lucidum ◽  
Hippocampal Neurons ◽  
Caspase 3 ◽  
Neuronal Damage ◽  
Tunel Staining ◽  
Ganoderma Lucidum Triterpenoids

Alzheimer’s disease (AD) is the most common cause of dementia among senior citizen. Ganoderma lucidum triterpenoids (GLTs) have nutritional health benefits and has been shown to promote health and longevity, but a protective effect of GLTs on AD damage has not yet been reported. The objective of this research was to elucidate the phylactic effect of GLTs on AD model mice and cells and to explore its underlying mechanisms. Morris water maze (MWM) test was conducted to detect changes in the cognitive function of mice. Hematoxylin-eosin (HE) staining was applied to observe pathological changes in the hippocampus. Silver nitrate staining was applied to observe the hippocampal neuronal tangles (NFTs). Apoptosis of the hippocampal neurons in mouse brain tissue was determined by TUNEL staining. The expression levels of apoptosis-related protein Bcl2, Bax, and caspase 3/cleaved caspase 3; antioxidative protein Nrf2, NQO1, and HO1; and ROCK signaling pathway-associated proteins ROCK2 and ROCK1 were measured by western blot. In vivo experiments show that 5-month-old APP/PS1 mice appeared to have impaired acquisition of spatial learning and GLTs could reduce cognitive impairment in AD mice. Compared to normal mice, the hippocampus of APP/PS1 mouse’s brains was severely damaged, while GLTs could alleviate this symptom by inhibiting apoptosis, relieving oxidative damage, and inactivating the ROCK signaling pathway. In in vitro cell experiments, Aβ25-35 was applied to induce hippocampal neurons into AD model cells. GLTs promoted cell proliferation, facilitated superoxide dismutase (SOD) expression, and inhibited malondialdehyde (MDA) and lactic dehydrogenase (LDH) expression of neurons. Our study highlights that GLTs improve cognitive impairment, alleviate neuronal damage, and inhibit apoptosis in the hippocampus tissues and cells in AD through inhibiting the ROCK signaling pathway.

scholarly journals Extracellular vesicles derived from human Wharton’s jelly mesenchymal stem cells protect hippocampal neurons from oxidative stress and synapse damage induced by amyloid-β oligomers

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Victor Bodart-Santos ◽  
Luiza R. P. de Carvalho ◽  
Mariana A. de Godoy ◽  
André F. Batista ◽  
Leonardo M. Saraiva ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Extracellular Vesicles ◽  
Hippocampal Neurons ◽  
Neuronal Damage ◽  
Wharton’S Jelly ◽  
Wharton's Jelly

Abstract Background Mesenchymal stem cells (MSCs) have been explored as promising tools for treatment of several neurological and neurodegenerative diseases. MSCs release abundant extracellular vesicles (EVs) containing a variety of biomolecules, including mRNAs, miRNAs, and proteins. We hypothesized that EVs derived from human Wharton’s jelly would act as mediators of the communication between hMSCs and neurons and could protect hippocampal neurons from damage induced by Alzheimer’s disease-linked amyloid beta oligomers (AβOs). Methods We isolated and characterized EVs released by human Wharton’s jelly mesenchymal stem cells (hMSC-EVs). The neuroprotective action of hMSC-EVs was investigated in primary hippocampal cultures exposed to AβOs. Results hMSC-EVs were internalized by hippocampal cells in culture, and this was enhanced in the presence of AβOs in the medium. hMSC-EVs protected hippocampal neurons from oxidative stress and synapse damage induced by AβOs. Neuroprotection by hMSC-EVs was mediated by catalase and was abolished in the presence of the catalase inhibitor, aminotriazole. Conclusions hMSC-EVs protected hippocampal neurons from damage induced by AβOs, and this was related to the transfer of enzymatically active catalase contained in EVs. Results suggest that hMSC-EVs should be further explored as a cell-free therapeutic approach to prevent neuronal damage in Alzheimer’s disease.

scholarly journals Loss of drebrin from dendritic spines in hippocampal neurons from Alzheimer's disease model mouse

2020 ◽  
Vol 93 (0) ◽  
pp. 2-P-135
Author(s):  
Noriko Koganezawa ◽  
Yuki Kajita ◽  
Hiroyuki Yamazaki ◽  
Takashi Saito ◽  
Yuko Sekino ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dendritic Spines ◽  
Hippocampal Neurons ◽  
Disease Model ◽  
Model Mouse

Seeding-Competent Tau in Gray Matter Versus White Matter of Alzheimer’s Disease Brain

2021 ◽  
Vol 79 (4) ◽  
pp. 1647-1659
Author(s):  
Ruozhen Wu ◽  
Jianlan Gu ◽  
Dingwei Zhou ◽  
Yunn Chyn Tung ◽  
Nana Jin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Gray Matter ◽  
Brain Regions ◽  
Hyperphosphorylated Tau ◽  
Tau Hyperphosphorylation ◽  
Brain Extracts ◽  
Axonal Compartment ◽  
Tau Aggregation

Background: Neurofibrillary pathology of abnormally hyperphosphorylated tau spreads along neuroanatomical connections, underlying the progression of Alzheimer’s disease (AD). The propagation of tau pathology to axonally connected brain regions inevitably involves trafficking of seeding-competent tau within the axonal compartment of the neuron. Objective: To determine the seeding activity of tau in cerebral gray and white matters of AD. Methods: Levels of total tau, hyperphosphorylation of tau, and SDS- and β-mercaptoethanol–resistant high molecular weight tau (HMW-tau) in crude extracts from gray and white matters of AD frontal lobes were analyzed by immuno-blots. Tau seeding activity was quantitatively assessed by measuring RIPA buffer–insoluble tau in HEK-293FT/tau151-391 cells treated with brain extracts. Results: We found a comparable level of soluble tau in gray matter versus white matter of control brains, but a higher level of soluble tau in gray matter than white matter of AD brains. In AD brains, tau is hyperphosphorylated in both gray and white matters, with a higher level in the former. The extracts of both gray and white matters of AD brains seeded tau aggregation in HEK-293FT/tau151–391 cells but the white matter showed less potency. Seeding activity of tau in brain extracts was positively correlated with the levels of tau hyperphosphorylation and HMW-tau. RIPA-insoluble tau, but not RIPA-soluble tau, was hyperphosphorylated tau at multiple sites. Conclusion: Both gray and white matters of AD brain contain seeding-competent tau that can template aggregation of hyperphosphorylated tau, but the seeding potency is markedly higher in gray matter than in white matter.

Fluoxetine Protects against Dendritic Spine Loss in Middle-aged APPswe/PSEN1dE9 Double Transgenic Alzheimer’s Disease Mice

2020 ◽  
Vol 17 (1) ◽  
pp. 93-103 ◽  
Author(s):  
Jing Ma ◽  
Yuan Gao ◽  
Wei Tang ◽  
Wei Huang ◽  
Yong Tang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dendritic Spines ◽  
Dendritic Spine ◽  
Early Stage ◽  
Learning Ability ◽  
Middle Aged ◽  
Protein Levels ◽  
Spine Pathology ◽  
The Impact

Background: Studies have suggested that cognitive impairment in Alzheimer’s disease (AD) is associated with dendritic spine loss, especially in the hippocampus. Fluoxetine (FLX) has been shown to improve cognition in the early stage of AD and to be associated with diminishing synapse degeneration in the hippocampus. However, little is known about whether FLX affects the pathogenesis of AD in the middle-tolate stage and whether its effects are correlated with the amelioration of hippocampal dendritic dysfunction. Previously, it has been observed that FLX improves the spatial learning ability of middleaged APP/PS1 mice. Objective: In the present study, we further characterized the impact of FLX on dendritic spines in the hippocampus of middle-aged APP/PS1 mice. Results: It has been found that the numbers of dendritic spines in dentate gyrus (DG), CA1 and CA2/3 of hippocampus were significantly increased by FLX. Meanwhile, FLX effectively attenuated hyperphosphorylation of tau at Ser396 and elevated protein levels of postsynaptic density 95 (PSD-95) and synapsin-1 (SYN-1) in the hippocampus. Conclusion: These results indicated that the enhanced learning ability observed in FLX-treated middle-aged APP/PS1 mice might be associated with remarkable mitigation of hippocampal dendritic spine pathology by FLX and suggested that FLX might be explored as a new strategy for therapy of AD in the middle-to-late stage.

Sign in / Sign up

Export Citation Format

Share Document