scholarly journals REDD1 Is Involved in Amyloid β-Induced Synaptic Dysfunction and Memory Impairment

2020 ◽  
Vol 21 (24) ◽  
pp. 9482
Author(s):  
Jee Hyun Yi ◽  
Huiyoung Kwon ◽  
Eunbi Cho ◽  
Jieun Jeon ◽  
Jeongwon Lee ◽  
...  
Keyword(s):  
Memory Impairment ◽  
Hippocampal Slices ◽  
Amyloid Β ◽  
Neurological Dysfunction ◽  
Synaptic Dysfunction ◽  
Hairpin Rna ◽  
Damage Response ◽  
Acute Hippocampal Slices ◽  
The Brain ◽  
Ad Therapy

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by neurological dysfunction, including memory impairment, attributed to the accumulation of amyloid β (Aβ) in the brain. Although several studies reported possible mechanisms involved in Aβ pathology, much remains unknown. Previous findings suggested that a protein regulated in development and DNA damage response 1 (REDD1), a stress-coping regulator, is an Aβ-responsive gene involved in Aβ cytotoxicity. However, we still do not know how Aβ increases the level of REDD1 and whether REDD1 mediates Aβ-induced synaptic dysfunction. To elucidate this, we examined the effect of Aβ on REDD1-expression using acute hippocampal slices from mice, and the effect of REDD1 short hairpin RNA (shRNA) on Aβ-induced synaptic dysfunction. Lastly, we observed the effect of REDD1 shRNA on memory deficit in an AD-like mouse model. Through the experiments, we found that Aβ-incubated acute hippocampal slices showed increased REDD1 levels. Moreover, Aβ injection into the lateral ventricle increased REDD1 levels in the hippocampus. Anisomycin, but not actinomycin D, blocked Aβ-induced increase in REDD1 levels in the acute hippocampal slices, suggesting that Aβ may increase REDD1 translation rather than transcription. Aβ activated Fyn/ERK/S6 cascade, and inhibitors for Fyn/ERK/S6 or mGluR5 blocked Aβ-induced REDD1 upregulation. REDD1 inducer, a transcriptional activator, and Aβ blocked synaptic plasticity in the acute hippocampal slices. REDD1 inducer inhibited mTOR/Akt signaling. REDD1 shRNA blocked Aβ-induced synaptic deficits. REDD1 shRNA also blocked Aβ-induced memory deficits in passive-avoidance and object-recognition tests. Collectively, these results demonstrate that REDD1 participates in Aβ pathology and could be a target for AD therapy.

scholarly journals Microglia-Based Sex-Biased Neuropathology in Early-Stage Alzheimer’s Disease Model Mice and the Potential Pharmacologic Efficacy of Dioscin

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3261
Author(s):  
Xiao Liu ◽  
Qian Zhou ◽  
Jia-He Zhang ◽  
Xiaoying Wang ◽  
Xiumei Gao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Disease Model ◽  
Amyloid Β ◽  
Brain Lesions ◽  
Synaptic Dysfunction ◽  
Synaptic Loss ◽  
And Function ◽  
The Brain

Alzheimer’s disease (AD), the most common form of dementia, is characterized by amyloid-β (Aβ) accumulation, microglia-associated neuroinflammation, and synaptic loss. The detailed neuropathologic characteristics in early-stage AD, however, are largely unclear. We evaluated the pathologic brain alterations in young adult App knock-in model AppNL-G-F mice at 3 and 6 months of age, which corresponds to early-stage AD. At 3 months of age, microglia expression in the cortex and hippocampus was significantly decreased. By the age of 6 months, the number and function of the microglia increased, accompanied by progressive amyloid-β deposition, synaptic dysfunction, neuroinflammation, and dysregulation of β-catenin and NF-κB signaling pathways. The neuropathologic changes were more severe in female mice than in male mice. Oral administration of dioscin, a natural product, ameliorated the neuropathologic alterations in young AppNL-G-F mice. Our findings revealed microglia-based sex-differential neuropathologic changes in a mouse model of early-stage AD and therapeutic efficacy of dioscin on the brain lesions. Dioscin may represent a potential treatment for AD.

scholarly journals Dendritic Localization and Exocytosis of NAAG in the Rat Hippocampus

2019 ◽  
Vol 30 (3) ◽  
pp. 1422-1435 ◽  
Author(s):  
K Nordengen ◽  
C Morland ◽  
B S Slusher ◽  
V Gundersen
Keyword(s):  
Hippocampal Slices ◽  
Retrograde Signaling ◽  
Glutamatergic Synapses ◽  
Toxin B ◽  
Close Proximity ◽  
Neuronal Stimulation ◽  
Low Levels ◽  
Acute Hippocampal Slices ◽  
Botulinum Toxin B ◽  
The Brain

Abstract While a lot is known about classical, anterograde neurotransmission, less is known about the mechanisms and molecules involved in retrograde neurotransmission. Our hypothesis is that N-acetylaspartylglutamate (NAAG), the most abundant dipeptide in the brain, may act as a retrograde transmitter in the brain. NAAG was predominantly localized in dendritic compartments of glutamatergic synapses in the intact hippocampus, where it was present in close proximity to synaptic-like vesicles. In acute hippocampal slices, NAAG was depleted from postsynaptic dendritic elements during neuronal stimulation induced by depolarizing concentrations of potassium or by exposure to glutamate receptor (GluR) agonists. The depletion was completely blocked by botulinum toxin B and strictly dependent on extracellular calcium, indicating exocytotic release. In contrast, there were low levels of NAAG and no effect by depolarization or GluR agonists in presynaptic glutamatergic terminals or GABAergic pre- and postsynaptic elements. Together these data suggest a possible role for NAAG as a retrograde signaling molecule at glutamatergic synapses via exocytotic release.

scholarly journals Minocycline reduces inflammatory parameters in the brain structures and serum and reverses memory impairment caused by the administration of amyloid β (1-42) in mice

2017 ◽  
Vol 77 ◽  
pp. 23-31 ◽  
Author(s):  
Michelle Lima Garcez ◽  
Francielle Mina ◽  
Tatiani Bellettini-Santos ◽  
Franciellen Gonçalves Carneiro ◽  
Aline Pereira Luz ◽  
...  
Keyword(s):  
Memory Impairment ◽  
Amyloid Β ◽  
Brain Structures ◽  
Inflammatory Parameters ◽  
The Brain

scholarly journals The glymphatic system and its role in the development of Alzheimer’s disease

2021 ◽  
Vol 8 (3) ◽  
pp. 14-21
Author(s):  
S. V. Vorobʼev ◽  
S. N. Yanishevskij
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Picture ◽  
Amyloid Β ◽  
Cognitive Disorders ◽  
Comprehensive Analysis ◽  
Synaptic Dysfunction ◽  
Glymphatic System ◽  
Neurodegenerative Pathology ◽  
The Brain

One of the main concepts explaining the development of Alzheimer’s disease is currently the amyloid theory. It was reliably established that the accumulation of the pathological protein amyloid β provokes the launch of a number of pathochemical reactions that ultimately lead to the development of synaptic dysfunction and the formation of cognitive disorders. The protein amyloid β is also synthesized in the brain of people who do not suffer from neurodegenerative pathology. Normally, it is actively removed from the brain. However, the exact mechanisms for maintaining its clearance are not established. The recently discovered glymphatic system claims to be such a component. The present review provides a comprehensive analysis of suggestions that the development of glymphatic system dysfunction contributes to the accumulation of amyloid β and the development of the clinical picture of Alzheimer›s disease.

Sulforaphane Reverses the Amyloid-β Oligomers Induced Depressive-Like Behavior

2020 ◽  
Vol 78 (1) ◽  
pp. 127-137 ◽  
Author(s):  
Wei Wang ◽  
Cuibai Wei ◽  
Meina Quan ◽  
Tingting Li ◽  
Jianping Jia
Keyword(s):  
Oxidative Stress ◽  
Memory Impairment ◽  
Molecular Mechanisms ◽  
Psychological Symptoms ◽  
Amyloid Β ◽  
Serotonergic System ◽  
Inflammatory Factors ◽  
The Relationship ◽  
The Brain ◽  
And Oxidative Stress

Background: Depression is one of the most common behavioral and psychological symptoms in people with Alzheimer’s disease (AD). To date, however, the molecular mechanisms underlying the clinical association between depression and AD remained elusive. Objective: Here, we study the relationship between memory impairment and depressive-like behavior in AD animal model, and investigate the potential mechanisms. Methods: Male SD rats were administered amyloid-β oligomers (AβOs) by intracerebroventricular injection, and then the depressive-like behavior, neuroinflammation, oxidative stress, and the serotonergic system were measured in the brain. Sulforaphane (SF), a compound with dual capacities of anti-inflammation and anti-oxidative stress, was injected intraperitoneally to evaluate the therapeutic effect. Results: The results showed that AβOs induced both memory impairment and depressive-like behavior in rats, through the mechanisms of inducing neuroinflammation and oxidative stress, and impairing the serotonergic axis. SF could reduce both inflammatory factors and oxidative stress parameters to protect the serotonergic system and alleviate memory impairment and depressive-like behavior in rats. Conclusion: These results provided insights into the biological mechanisms underlying the clinical link between depressive disorder and AD, and offered new drug options for the treatment of depressive symptoms in dementia.

scholarly journals From Stroke to Dementia: a Comprehensive Review Exposing Tight Interactions Between Stroke and Amyloid-β Formation

2019 ◽  
Vol 11 (4) ◽  
pp. 601-614 ◽  
Author(s):  
Romain Goulay ◽  
Luis Mena Romo ◽  
Elly M. Hol ◽  
Rick M. Dijkhuizen
Keyword(s):  
Cerebrovascular Disease ◽  
Case Reports ◽  
Amyloid Β ◽  
Brain Parenchyma ◽  
Perivascular Space ◽  
Synaptic Dysfunction ◽  
Amyloid Angiopathy ◽  
Cerebral Vessel ◽  
The Brain ◽  
Apparent Association

AbstractStroke and Alzheimer’s disease (AD) are cerebral pathologies with high socioeconomic impact that can occur together and mutually interact. Vascular factors predisposing to cerebrovascular disease have also been specifically associated with development of AD, and acute stroke is known to increase the risk to develop dementia.Despite the apparent association, it remains unknown how acute cerebrovascular disease and development of AD are precisely linked and act on each other. It has been suggested that this interaction is strongly related to vascular deposition of amyloid-β (Aβ), i.e., cerebral amyloid angiopathy (CAA). Furthermore, the blood–brain barrier (BBB), perivascular space, and the glymphatic system, the latter proposedly responsible for the drainage of solutes from the brain parenchyma, may represent key pathophysiological pathways linking stroke, Aβ deposition, and dementia.In this review, we propose a hypothetic connection between CAA, stroke, perivascular space integrity, and dementia. Based on relevant pre-clinical research and a few clinical case reports, we speculate that impaired perivascular space integrity, inflammation, hypoxia, and BBB breakdown after stroke can lead to accelerated deposition of Aβ within brain parenchyma and cerebral vessel walls or exacerbation of CAA. The deposition of Aβ in the parenchyma would then be the initiating event leading to synaptic dysfunction, inducing cognitive decline and dementia. Maintaining the clearance of Aβ after stroke could offer a new therapeutic approach to prevent post-stroke cognitive impairment and development into dementia.

Neoline Improves Memory Impairment and Reduces Amyloid-β Level and Tau Phosphorylation Through AMPK Activation in the Mouse Alzheimer’s Disease Model

2021 ◽  
pp. 1-10
Author(s):  
Quan Feng Liu ◽  
Suganya Kanmani ◽  
Jinhyuk Lee ◽  
Geun-Woo Kim ◽  
Songhee Jeon ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Memory Impairment ◽  
Amyloid Β ◽  
Chronic Administration ◽  
Therapeutic Effects ◽  
Ampk Activation ◽  
The Brain ◽  
Ad Mouse Model

Background: Alzheimer’s disease (AD) is the most general, chronic, and progressive neurodegenerative senile disorder characterized clinically by progressive cognitive deterioration and memory impairment. Neoline is effective against neuropathic pain models, but the effects of neoline against AD-like phenotypes have not been investigated. Objective: We offer the investigation of the effects of neoline in AD. Methods: In this study, a Tg-APPswe/PS1dE9 AD mouse model was treated orally with neoline at a concentration of 0.5 mg/kg or 0.1 mg/kg starting at 7.5 months and administered for three months, and its anti-AD effects were evaluated. Results: Neoline improved memory and cognition impairments and reduced the number of amyloid-beta plaque and the amount of amyloid-β in the brain of AD mice. Furthermore, neoline reduced the anxiety behavior in the AD mouse model. The chronic administration of neoline also induced AMPK phosphorylation and decreased tau, amyloid-β, and BACE1 expression in the hippocampus. These findings indicate that chronic administration of neoline has therapeutic effects via AMPK activation, and BACE1 downregulation resulted in a decrease in the amyloid-β levels in the brain of Tg-APPswe/PS1dE9 AD mice. Conclusion: Our results suggest that neoline is a therapeutic agent for the cure of neurodegenerative diseases like AD.

scholarly journals The role of pathological tau in synaptic dysfunction in Alzheimer’s diseases

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Moxin Wu ◽  
Manqing Zhang ◽  
Xiaoping Yin ◽  
Kai Chen ◽  
Zhijian Hu ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Dendritic Spines ◽  
Amyloid Β ◽  
Synaptic Function ◽  
Synaptic Dysfunction ◽  
Novel Therapeutic Strategies ◽  
And Function ◽  
The Brain ◽  
Pathological Event

AbstractAlzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, accompanied by amyloid-β (Aβ) overload and hyperphosphorylated tau accumulation in the brain. Synaptic dysfunction, an important pathological hallmark in AD, is recognized as the main cause of the cognitive impairments. Accumulating evidence suggests that synaptic dysfunction could be an early pathological event in AD. Pathological tau, which is detached from axonal microtubules and mislocalized into pre- and postsynaptic neuronal compartments, is suggested to induce synaptic dysfunction in several ways, including reducing mobility and release of presynaptic vesicles, decreasing glutamatergic receptors, impairing the maturation of dendritic spines at postsynaptic terminals, disrupting mitochondrial transport and function in synapses, and promoting the phagocytosis of synapses by microglia. Here, we review the current understanding of how pathological tau mediates synaptic dysfunction and contributes to cognitive decline in AD. We propose that elucidating the mechanism by which pathological tau impairs synaptic function is essential for exploring novel therapeutic strategies for AD.

scholarly journals Night Photostimulation of Clearance of Beta-Amyloid from Mouse Brain: New Strategies in Preventing Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3289
Author(s):  
Oxana Semyachkina-Glushkovskaya ◽  
Thomas Penzel ◽  
Inna Blokhina ◽  
Alexander Khorovodov ◽  
Ivan Fedosov ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Elderly Age ◽  
Clearing Functions ◽  
Aβ Clearance ◽  
The Brain ◽  
Ad Therapy ◽  
New Strategies ◽  
Stimulation Of

The deposition of amyloid-β (Aβ) in the brain is a risk factor for Alzheimer’s disease (AD). Therefore, new strategies for the stimulation of Aβ clearance from the brain can be useful in preventing AD. Transcranial photostimulation (PS) is considered a promising method for AD therapy. In our previous studies, we clearly demonstrated the PS-mediated stimulation of lymphatic clearing functions, including Aβ removal from the brain. There is increasing evidence that sleep plays an important role in Aβ clearance. Here, we tested our hypothesis that PS at night can stimulate Aβ clearance from the brain more effectively than PS during the day. Our results on healthy mice show that Aβ clearance from the brain occurs faster at night than during wakefulness. The PS course at night improves memory and reduces Aβ accumulation in the brain of AD mice more effectively than the PS course during the day. Our results suggest that night PS is a more promising candidate as an effective method in preventing AD than daytime PS. These data are an important informative platform for the development of new noninvasive and nonpharmacological technologies for AD therapy as well as for preventing Aβ accumulation in the brain of people with disorder of Aβ metabolism, sleep deficit, elderly age, and jet lag.

scholarly journals Natural Medicines and Their Underlying Mechanisms of Prevention and Recovery from Amyloid Β-Induced Axonal Degeneration in Alzheimer’s Disease

2020 ◽  
Vol 21 (13) ◽  
pp. 4665
Author(s):  
Tomoharu Kuboyama ◽  
Ximeng Yang ◽  
Chihiro Tohda
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Network ◽  
Memory Impairment ◽  
Axonal Degeneration ◽  
Memory Function ◽  
Amyloid Β ◽  
In Vivo Models ◽  
Network Disruption ◽  
Ad Therapy

In Alzheimer’s disease (AD), amyloid β (Aβ) induces axonal degeneration, neuronal network disruption, and memory impairment. Although many candidate drugs to reduce Aβ have been clinically investigated, they failed to recover the memory function in AD patients. Reportedly, Aβ deposition occurred before the onset of AD. Once neuronal networks were disrupted by Aβ, they could hardly be recovered. Therefore, we speculated that only removal of Aβ was not enough for AD therapy, and prevention and recovery from neuronal network disruption were also needed. This review describes the challenges related to the condition of axons for AD therapy. We established novel in vitro models of Aβ-induced axonal degeneration. Using these models, we found that several traditional medicines and their constituents prevented or helped recover from Aβ-induced axonal degeneration. These drugs also prevented or helped recover from memory impairment in in vivo models of AD. One of these drugs ameliorated memory decline in AD patients in a clinical study. These results indicate that prevention and recovery from axonal degeneration are possible strategies for AD therapy.

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