scholarly journals NHE6-depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Theresa Pohlkamp ◽  
Xunde Xian ◽  
Connie H Wong ◽  
Murat S Durakoglugil ◽  
Gordon Chandler Werthmann ◽  
...  
Keyword(s):  
Late Onset ◽  
Amyloid Plaque ◽  
Vesicular Trafficking ◽  
Synaptic Homeostasis ◽  
Sodium Hydrogen ◽  
Early Endosomes ◽  
Endosomal Acidification ◽  
Sodium Hydrogen Exchanger ◽  
Plaque Load ◽  
The Brain

Apolipoprotein E4 (ApoE4) is the most important and prevalent risk factor for late-onset Alzheimer's disease (AD). The isoelectric point of ApoE4 matches the pH of the early endosome (EE), causing its delayed dissociation from ApoE receptors and hence impaired endolysosomal trafficking, disruption of synaptic homeostasis and reduced amyloid clearance. We have shown that enhancing endosomal acidification by inhibiting the EE-specific sodium-hydrogen exchanger 6 (NHE6) restores vesicular trafficking and normalizes synaptic homeostasis. Remarkably and unexpectedly, loss of NHE6 (encoded by the gene Slc9a6) in mice effectively suppressed amyloid deposition even in the absence of ApoE4, suggesting that accelerated acidification of early endosomes caused by the absence of NHE6 occludes the effect of ApoE on amyloid plaque formation. NHE6 suppression or inhibition may thus be a universal, ApoE-independent approach to prevent amyloid buildup in the brain. These findings suggest a novel therapeutic approach for the prevention of AD by which partial NHE6 inhibition reverses the ApoE4 induced endolysosomal trafficking defect and reduces plaque load.

scholarly journals Endosomal Acidification by NHE6-depletion Corrects ApoE4-mediated Synaptic Impairments and Reduces Amyloid Plaque Load

2021 ◽  
Author(s):  
Theresa Pohlkamp ◽  
Xunde Xian ◽  
Connie H Wong ◽  
Murat Durakoglugil ◽  
Takaomi Saido ◽  
...  
Keyword(s):  
Late Onset ◽  
Amyloid Plaque ◽  
Plaque Formation ◽  
Vesicular Trafficking ◽  
Synaptic Homeostasis ◽  
Sodium Hydrogen ◽  
Activated State ◽  
Endosomal Acidification ◽  
Sodium Hydrogen Exchanger ◽  
Plaque Load

ABSTRACTApolipoprotein E4 (ApoE4) is the most important and prevalent risk factor for late-onset Alzheimer’s disease (AD). The isoelectric point of ApoE4 matches the pH of the early endosome (EE), causing its delayed dissociation from ApoE receptors and hence impaired endolysosomal trafficking, disruption of synaptic homeostasis and reduced amyloid clearance. We have shown that enhancing endosomal acidification by inhibiting the EE-specific sodium-hydrogen exchanger NHE6 restores vesicular trafficking and normalizes synaptic homeostasis. Using NHE6 conditional KO mice we now also show that disruption of NHE6 activates the resident microglia and thus reduces early and advanced amyloid plaque formation in humanized APPNL-F knockin mice in the presence or absence of ApoE4 by approximately 80%. These findings suggest a novel therapeutic approach for the prevention of AD by which partial NHE6 inhibition reverses the ApoE4 induced endolysosomal trafficking defect, while at the same time shifting the resident microglia from the dormant, homeostatic to the damage-associated, activated state.

scholarly journals Astrocyte-derived clusterin suppresses amyloid formation in vivo

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Aleksandra M. Wojtas ◽  
Jonathon P. Sens ◽  
Silvia S. Kang ◽  
Kelsey E. Baker ◽  
Taylor J. Berry ◽  
...  
Keyword(s):  
Gene Delivery ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Amyloid Formation ◽  
Plaque Load ◽  
Amyloid Load ◽  
Or Gene ◽  
And Control ◽  
The Brain

Abstract Background Accumulation of amyloid-β (Aβ) peptide in the brain is a pathological hallmark of Alzheimer’s disease (AD). The clusterin (CLU) gene confers a risk for AD and CLU is highly upregulated in AD patients, with the common non-coding, protective CLU variants associated with increased expression. Although there is strong evidence implicating CLU in amyloid metabolism, the exact mechanism underlying the CLU involvement in AD is not fully understood or whether physiologic alterations of CLU levels in the brain would be protective. Results We used a gene delivery approach to overexpress CLU in astrocytes, the major source of CLU expression in the brain. We found that CLU overexpression resulted in a significant reduction of total and fibrillar amyloid in both cortex and hippocampus in the APP/PS1 mouse model of AD amyloidosis. CLU overexpression also ameliorated amyloid-associated neurotoxicity and gliosis. To complement these overexpression studies, we also analyzed the effects of haploinsufficiency of Clu using heterozygous (Clu+/−) mice and control littermates in the APP/PS1 model. CLU reduction led to a substantial increase in the amyloid plaque load in both cortex and hippocampus in APP/PS1; Clu+/− mice compared to wild-type (APP/PS1; Clu+/+) littermate controls, with a concomitant increase in neuritic dystrophy and gliosis. Conclusions Thus, both physiologic ~ 30% overexpression or ~ 50% reduction in CLU have substantial impacts on amyloid load and associated pathologies. Our results demonstrate that CLU plays a major role in Aβ accumulation in the brain and suggest that efforts aimed at CLU upregulation via pharmacological or gene delivery approaches offer a promising therapeutic strategy to regulate amyloid pathology.

scholarly journals CYP46A1 Activation by Efavirenz Leads to Behavioral Improvement without Significant Changes in Amyloid Plaque Load in the Brain of 5XFAD Mice

2019 ◽  
Vol 16 (3) ◽  
pp. 710-724 ◽  
Author(s):  
Alexey M. Petrov ◽  
Morrie Lam ◽  
Natalia Mast ◽  
Jean Moon ◽  
Yong Li ◽  
...  
Keyword(s):  
Amyloid Plaque ◽  
Plaque Load ◽  
5Xfad Mice ◽  
Behavioral Improvement ◽  
The Brain

Current Strategies and Novel Drug Approaches for Alzheimer Disease

2020 ◽  
Vol 19 (9) ◽  
pp. 676-690 ◽  
Author(s):  
Roma Ghai ◽  
Kandasamy Nagarajan ◽  
Meenakshi Arora ◽  
Parul Grover ◽  
Nazakat Ali ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cholinergic Neurons ◽  
Amyloid Plaque ◽  
Neural Pathways ◽  
Current Trends ◽  
Personality Changes ◽  
Traditional Therapies ◽  
Novel Drug ◽  
The Brain

Alzheimer’s Disease (AD) is a chronic, devastating dysfunction of neurons in the brain leading to dementia. It mainly arises due to neuronal injury in the cerebral cortex and hippocampus area of the brain and is clinically manifested as a progressive mental failure, disordered cognitive functions, personality changes, reduced verbal fluency and impairment of speech. The pathology behind AD is the formation of intraneuronal fibrillary tangles, deposition of amyloid plaque and decline in choline acetyltransferase and loss of cholinergic neurons. Tragically, the disease cannot be cured, but its progression can be halted. Various cholinesterase inhibitors available in the market like Tacrine, Donepezil, Galantamine, Rivastigmine, etc. are being used to manage the symptoms of Alzheimer’s disease. The paper’s objective is to throw light not only on the cellular/genetic basis of the disease, but also on the current trends and various strategies of treatment including the use of phytopharmaceuticals and nutraceuticals. Enormous literature survey was conducted and published articles of PubMed, Scifinder, Google Scholar, Clinical Trials.org and Alzheimer Association reports were studied intensively to consolidate the information on the strategies available to combat Alzheimer’s disease. Currently, several strategies are being investigated for the treatment of Alzheimer’s disease. Immunotherapies targeting amyloid-beta plaques, tau protein and neural pathways are undergoing clinical trials. Moreover, antisense oligonucleotide methodologies are being approached as therapies for its management. Phytopharmaceuticals and nutraceuticals are also gaining attention in overcoming the symptoms related to AD. The present review article concludes that novel and traditional therapies simultaneously promise future hope for AD treatment.

scholarly journals Bacterial sepsis increases hippocampal fibrillar amyloid plaque load and neuroinflammation in a mouse model of Alzheimer's disease

2021 ◽  
Vol 152 ◽  
pp. 105292
Author(s):  
Jacob M. Basak ◽  
Aura Ferreiro ◽  
Lucy S. Cohen ◽  
Patrick W. Sheehan ◽  
Collin J. Nadarajah ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Amyloid Plaque ◽  
Bacterial Sepsis ◽  
Model Of Alzheimer’S Disease ◽  
Plaque Load

scholarly journals Screening of 5- and 6-Substituted Amiloride Libraries Identifies Dual-uPA/NHE1 Active and Single Target-Selective Inhibitors

2021 ◽  
Vol 22 (6) ◽  
pp. 2999
Author(s):  
Benjamin J. Buckley ◽  
Ashna Kumar ◽  
Ashraf Aboelela ◽  
Richard S. Bujaroski ◽  
Xiuju Li ◽  
...  
Keyword(s):  
Selectivity Ratio ◽  
Dual Targeting ◽  
Sodium Hydrogen ◽  
Type Plasminogen Activator ◽  
Single Target ◽  
Urokinase Type Plasminogen Activator ◽  
Anti Cancer ◽  
Sodium Hydrogen Exchanger ◽  
A Cell ◽  
Cell Invasiveness

The K+-sparing diuretic amiloride shows off-target anti-cancer effects in multiple rodent models. These effects arise from the inhibition of two distinct cancer targets: the trypsin-like serine protease urokinase-type plasminogen activator (uPA), a cell-surface mediator of matrix degradation and tumor cell invasiveness, and the sodium-hydrogen exchanger isoform-1 (NHE1), a central regulator of transmembrane pH that supports carcinogenic progression. In this study, we co‑screened our library of 5- and 6-substituted amilorides against these two targets, aiming to identify single-target selective and dual-targeting inhibitors for use as complementary pharmacological probes. Closely related analogs substituted at the 6-position with pyrimidines were identified as dual-targeting (pyrimidine 24 uPA IC50 = 175 nM, NHE1 IC50 = 266 nM, uPA selectivity ratio = 1.5) and uPA-selective (methoxypyrimidine 26 uPA IC50 = 86 nM, NHE1 IC50 = 12,290 nM, uPA selectivity ratio = 143) inhibitors, while high NHE1 potency and selectivity was seen with 5-morpholino (29 NHE1 IC50 = 129 nM, uPA IC50 = 10,949 nM; NHE1 selectivity ratio = 85) and 5-(1,4-oxazepine) (30 NHE1 IC50 = 85 nM, uPA IC50 = 5,715 nM; NHE1 selectivity ratio = 67) analogs. Together, these amilorides comprise a new toolkit of chemotype-matched, non-cytotoxic probes for dissecting the pharmacological effects of selective uPA and NHE1 inhibition versus dual-uPA/NHE1 inhibition.

scholarly journals Time to Be SHY? Some Comments on Sleep and Synaptic Homeostasis

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Giulio Tononi ◽  
Chiara Cirelli
Keyword(s):  
Synaptic Strength ◽  
Universal Function ◽  
Systematic Bias ◽  
Synaptic Homeostasis ◽  
The Face ◽  
Essential Function ◽  
Function Of Sleep ◽  
The Brain

Sleep must serve an essential, universal function, one that offsets the risk of being disconnected from the environment. The synaptic homeostasis hypothesis (SHY) is an attempt to identify this essential function. Its core claim is that sleep is needed to reestablish synaptic homeostasis, which is challenged by the remarkable plasticity of the brain. In other words, sleep is “the price we pay for plasticity.” In this issue, M. G. Frank reviewed several aspects of the hypothesis and raised several issues. The comments below provide a brief summary of the motivations underlying SHY and clarify that SHY is a hypothesis not about specific mechanisms, but about a universal, essential function of sleep. This function is the preservation of synaptic homeostasis in the face of a systematic bias toward a net increase in synaptic strength—a challenge that is posed by learning during adult wake, and by massive synaptogenesis during development.

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