Emodin inhibits aggregation of amyloid‐β peptide 1–42 and improves cognitive deficits in Alzheimer's disease transgenic mice

2020 ◽  
Author(s):  
Lichun Wang ◽  
Sitong Liu ◽  
Jiaqi Xu ◽  
Nobumoto Watanabe ◽  
Kevin H. Mayo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Cognitive Deficits ◽  
Amyloid Β ◽  
Amyloid Β Peptide

scholarly journals Behavioral and neural network abnormalities in human APP transgenic mice resemble those of App knock-in mice and are modulated by familial Alzheimer’s disease mutations but not by inhibition of BACE1

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Erik C. B. Johnson ◽  
Kaitlyn Ho ◽  
Gui-Qiu Yu ◽  
Melanie Das ◽  
Pascal E. Sanchez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Neurodegenerative Disorder ◽  
Epileptiform Activity ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Aβ Oligomers ◽  
Behavioral Abnormalities ◽  
Amyloid Deposits

Abstract Background Alzheimer’s disease (AD) is the most frequent and costly neurodegenerative disorder. Although diverse lines of evidence suggest that the amyloid precursor protein (APP) is involved in its causation, the precise mechanisms remain unknown and no treatments are available to prevent or halt the disease. A favorite hypothesis has been that APP contributes to AD pathogenesis through the cerebral accumulation of the amyloid-β peptide (Aβ), which is derived from APP through sequential proteolytic cleavage by BACE1 and γ-secretase. However, inhibitors of these enzymes have failed in clinical trials despite clear evidence for target engagement. Methods To further elucidate the roles of APP and its metabolites in AD pathogenesis, we analyzed transgenic mice overexpressing wildtype human APP (hAPP) or hAPP carrying mutations that cause autosomal dominant familial AD (FAD), as well as App knock-in mice that do not overexpress hAPP but have two mouse App alleles with FAD mutations and a humanized Aβ sequence. Results Although these lines of mice had marked differences in cortical and hippocampal levels of APP, APP C-terminal fragments, soluble Aβ, Aβ oligomers and age-dependent amyloid deposition, they all developed cognitive deficits as well as non-convulsive epileptiform activity, a type of network dysfunction that also occurs in a substantive proportion of humans with AD. Pharmacological inhibition of BACE1 effectively reduced levels of amyloidogenic APP C-terminal fragments (C99), soluble Aβ, Aβ oligomers, and amyloid deposits in transgenic mice expressing FAD-mutant hAPP, but did not improve their network dysfunction and behavioral abnormalities, even when initiated at early stages before amyloid deposits were detectable. Conclusions hAPP transgenic and App knock-in mice develop similar pathophysiological alterations. APP and its metabolites contribute to AD-related functional alterations through complex combinatorial mechanisms that may be difficult to block with BACE inhibitors and, possibly, also with other anti-Aβ treatments.

scholarly journals Coexistence of amyloid-β and Tau hyperphosphorylation rescues cognitive and electrophysiological deficiencies in a mouse model of Alzheimer’s disease

2020 ◽  
Author(s):  
Eva Dávila-Bouziguet ◽  
Arnau Casòliba-Melich ◽  
Georgina Targa-Fabra ◽  
Lorena Galera-López ◽  
Andrés Ozaita ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Activity ◽  
Cognitive Deficits ◽  
Amyloid Β ◽  
Pyramidal Cells ◽  
Amyloid Β Peptide ◽  
Model Of Alzheimer’S Disease ◽  
Phosphorylation Pattern ◽  
Hippocampal Theta

AbstractAlzheimer’s disease hallmarks include amyloid-β peptide (Aβ) and hyperphosphorylated Tau (P-Tau), abnormalities in hippocampal oscillatory rhythms, imbalance of neuronal activity, and cognitive deficits. J20 and VLW mice, accumulating Aβ and P-Tau, respectively, show imbalanced neuronal activity and cognitive impairments. Here we analyzed mice simultaneously accumulating Aβ and P-Tau (J20/VLW). No changes in Aβ load or in P-Tau in pyramidal cells were observed in J20/VLW animals compared to respective single transgenic models. Conversely, the density of hippocampal interneurons accumulating pThr205 and pSer262 Tau was higher in J20/VLW than in VLW mice. The GABAergic septohippocampal (SH) connection specifically innervates hippocampal interneurons, modulating hippocampal electrophysiology. Contrarily to previous results showing an important reduction of GABAergic SH innervation in J20 and VLW mice, here we demonstrate that the GABAergic SH connection is preserved in J20/VLW animals. Furthermore, our findings indicate that hippocampal theta rhythms, markedly diminished in J20 and VLW mice, are partially rescued in J20/VLW animals. Moreover, the simultaneous presence of Aβ and P-Tau rescues Aβ-associated recognition memory deficits in J20/VLW mice. Altogether, these data suggest that a differential Tau phosphorylation pattern in hippocampal interneurons protects against loss of GABAergic SH innervation, preventing alterations in local field potentials and avoiding cognitive deficits.

Amyloid β-peptide and Alzheimer's disease

2014 ◽  
Vol 56 ◽  
pp. 99-110 ◽  
Author(s):  
David Allsop ◽  
Jennifer Mayes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Strong Support ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Cascade Hypothesis ◽  
Sequence Of Events ◽  
Aβ Amyloid ◽  
Amyloid Cascade

One of the hallmarks of AD (Alzheimer's disease) is the formation of senile plaques in the brain, which contain fibrils composed of Aβ (amyloid β-peptide). According to the ‘amyloid cascade’ hypothesis, the aggregation of Aβ initiates a sequence of events leading to the formation of neurofibrillary tangles, neurodegeneration, and on to the main symptom of dementia. However, emphasis has now shifted away from fibrillar forms of Aβ and towards smaller and more soluble ‘oligomers’ as the main culprit in AD. The present chapter commences with a brief introduction to the disease and its current treatment, and then focuses on the formation of Aβ from the APP (amyloid precursor protein), the genetics of early-onset AD, which has provided strong support for the amyloid cascade hypothesis, and then on the development of new drugs aimed at reducing the load of cerebral Aβ, which is still the main hope for providing a more effective treatment for AD in the future.

MiR-335-5p Inhibits β-Amyloid (Aβ) Accumulation to Attenuate Cognitive Deficits Through Targeting c-jun-N-terminal Kinase 3 in Alzheimer’s Disease

2020 ◽  
Vol 17 (1) ◽  
pp. 93-101 ◽  
Author(s):  
Dan Wang ◽  
Zhifu Fei ◽  
Song Luo ◽  
Hai Wang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Western Blot ◽  
Mrna Expression ◽  
Cognitive Deficits ◽  
Protein Levels ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
The Relationship

Objectives: Alzheimer's disease (AD), also known as senile dementia, is a common neurodegenerative disease characterized by progressive cognitive impairment and personality changes. Numerous evidences have suggested that microRNAs (miRNAs) are involved in the pathogenesis and development of AD. However, the exact role of miR-335-5p in the progression of AD is still not clearly clarified. Methods: The protein and mRNA levels were measured by western blot and RNA extraction and quantitative real-time PCR (qRT-PCR), respectively. The relationship between miR-335-5p and c-jun-N-terminal kinase 3 (JNK3) was confirmed by dual-luciferase reporter assay. SH-SY5Y cells were transfected with APP mutant gene to establish the in vitro AD cell model. Flow cytometry and western blot were performed to evaluate cell apoptosis. The APP/PS1 transgenic mice were used as an in vivo AD model. Morris water maze test was performed to assess the effect of miR- 335-5p on the cognitive deficits in APP/PS1 transgenic mice. Results: The JNK3 mRNA expression and protein levels of JNK3 and β-Amyloid (Aβ) were significantly up-regulated, and the mRNA expression of miR-335-5p was down-regulated in the brain tissues of AD patients. The expression levels of miR-335-5p and JNK3 were significantly inversely correlated. Further, the dual Luciferase assay verified the relationship between miR-335- 5p and JNK3. Overexpression of miR-335-5p significantly decreased the protein levels of JNK3 and Aβ and inhibited apoptosis in SH-SY5Y/APPswe cells, whereas the inhibition of miR-335-5p obtained the opposite results. Moreover, the overexpression of miR-335-5p remarkably improved the cognitive abilities of APP/PS1 mice. Conclusion: The results revealed that the increased JNK3 expression, negatively regulated by miR-335-5p, may be a potential mechanism that contributes to Aβ accumulation and AD progression, indicating a novel approach for AD treatment.

Is it All Said for NSAIDs in Alzheimer’s Disease? Role of Mitochondrial Calcium Uptake

2018 ◽  
Vol 15 (6) ◽  
pp. 504-510 ◽  
Author(s):  
Sara Sanz-Blasco ◽  
Maria Calvo-Rodríguez ◽  
Erica Caballero ◽  
Monica Garcia-Durillo ◽  
Lucia Nunez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Amyloid Β ◽  
Epidemiological Data ◽  
Amyloid Β Peptide ◽  
Aβ Oligomers ◽  
Mitochondrial Potential ◽  
Disease Modifying Drugs ◽  
Definitive Evidence

Objectives: Epidemiological data suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD). Unfortunately, recent trials have failed in providing compelling evidence of neuroprotection. Discussion as to why NSAIDs effectivity is uncertain is ongoing. Possible explanations include the view that NSAIDs and other possible disease-modifying drugs should be provided before the patients develop symptoms of AD or cognitive decline. In addition, NSAID targets for neuroprotection are unclear. Both COX-dependent and independent mechanisms have been proposed, including γ-secretase that cleaves the amyloid precursor protein (APP) and yields amyloid β peptide (Aβ). Methods: We have proposed a neuroprotection mechanism for NSAIDs based on inhibition of mitochondrial Ca2+ overload. Aβ oligomers promote Ca2+ influx and mitochondrial Ca2+ overload leading to neuron cell death. Several non-specific NSAIDs including ibuprofen, sulindac, indomethacin and Rflurbiprofen depolarize mitochondria in the low µM range and prevent mitochondrial Ca2+ overload induced by Aβ oligomers and/or N-methyl-D-aspartate (NMDA). However, at larger concentrations, NSAIDs may collapse mitochondrial potential (ΔΨ) leading to cell death. Results: Accordingly, this mechanism may explain neuroprotection at low concentrations and damage at larger doses, thus providing clues on the failure of promising trials. Perhaps lower NSAID concentrations and/or alternative compounds with larger dynamic ranges should be considered for future trials to provide definitive evidence of neuroprotection against AD.

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