scholarly journals MicroRNA-132 provides neuroprotection for tauopathies via multiple signaling pathways

2018 ◽  
Author(s):  
Rachid El Fatimy ◽  
Shaomin Li ◽  
Zhicheng Chen ◽  
Tasnim Mushannen ◽  
Sree Gongala ◽  
...  
Keyword(s):  
Rna Binding ◽  
Amyloid Β ◽  
Long Term Potentiation ◽  
Therapeutic Benefit ◽  
Glutamate Excitotoxicity ◽  
Amyloid Β Peptide ◽  
Neuroprotective Effects ◽  
Term Potentiation ◽  
Neuroprotective Function ◽  
Multiple Signaling

AbstractMicroRNAs (miRNA) regulate fundamental biological processes, including neuronal plasticity, stress response, and survival. Here we describe a neuroprotective function of miR-132, the miRNA most significantly down-regulated in Alzheimer’s disease. miR-132 protects mouse and human wild-type neurons and more vulnerable Tau-mutant primary neurons against amyloid β-peptide (Aβ) and glutamate excitotoxicity. It lowers the levels of total, phosphorylated, acetylated, and cleaved forms of Tau implicated in tauopathies, promotes neurite elongation and branching, and reduces neuronal death. Similarly, miR-132 attenuates PHF Tau pathology and neurodegeneration and enhances long-term potentiation in the P301S Tau transgenic mice. The neuroprotective effects are mediated by direct regulation of the Tau modifiers acetyltransferase EP300, kinase GSK3β, RNA-binding protein Rbfox1, and proteases Calpain 2 and Caspases 3/7. These data suggest miR-132 as a master regulator of neuronal health and indicate that miR-132 supplementation could be of therapeutic benefit for the treatment of Tau-associated neurodegenerative disorders.

scholarly journals Amyloid-β Peptide Is Needed for cGMP-Induced Long-Term Potentiation and Memory

2017 ◽  
Vol 37 (29) ◽  
pp. 6926-6937 ◽  
Author(s):  
Agostino Palmeri ◽  
Roberta Ricciarelli ◽  
Walter Gulisano ◽  
Daniela Rivera ◽  
Claudia Rebosio ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Long Term Potentiation ◽  
Amyloid Β Peptide ◽  
Term Potentiation

DCP-LA neutralizes mutant amyloid β peptide-induced impairment of long-term potentiation and spatial learning

2010 ◽  
Vol 206 (1) ◽  
pp. 151-154 ◽  
Author(s):  
Tetsu Nagata ◽  
Takemi Tominaga ◽  
Hiroshi Mori ◽  
Takahiro Yaguchi ◽  
Tomoyuki Nishizaki
Keyword(s):  
Spatial Learning ◽  
Amyloid Β ◽  
Long Term Potentiation ◽  
Amyloid Β Peptide ◽  
Term Potentiation

scholarly journals Neuronal Aβ42 is enriched in small vesicles at the presynaptic side of synapses

2018 ◽  
Vol 1 (3) ◽  
pp. e201800028 ◽  
Author(s):  
Yang Yu ◽  
Daniel C Jans ◽  
Bengt Winblad ◽  
Lars O Tjernberg ◽  
Sophia Schedin-Weiss
Keyword(s):  
Hippocampal Neurons ◽  
Memory Function ◽  
Three Dimensional ◽  
Amyloid Β ◽  
Super Resolution ◽  
Long Term Potentiation ◽  
Synaptic Function ◽  
Amyloid Β Peptide ◽  
Term Potentiation ◽  
Super Resolution Microscopy

The amyloid β-peptide (Aβ) is a physiological ubiquitously expressed peptide suggested to be involved in synaptic function, long-term potentiation, and memory function. The 42 amino acid-long variant (Aβ42) forms neurotoxic oligomers and amyloid plaques and plays a key role in the loss of synapses and other pathogenic events of Alzheimer disease. Still, the exact localization of Aβ42 in neurons and at synapses has not been reported. Here, we used super-resolution microscopy and show that Aβ42 was present in small vesicles in presynaptic compartments, but not in postsynaptic compartments, in the neurites of hippocampal neurons. Some of these vesicles appeared to lack synaptophysin, indicating that they differ from the synaptic vesicles responsible for neurotransmitter release. The Aβ42-containing vesicles existed in presynapses connected to stubby spines and mushroom spines, and were also present in immature presynapses. These vesicles were scarce in other parts of the neurites, where Aβ42 was instead present in large, around 200–600 nm, vesicular structures. Three-dimensional super-resolution microscopy confirmed that Aβ42 was present in the presynapse and absent in the postsynapse.

scholarly journals Genetic Depletion of Amylin/Calcitonin Receptors Improves Memory and Learning in Transgenic Alzheimer’s Disease Mouse Models.

2021 ◽  
Author(s):  
Aarti Patel ◽  
Ryoichi Kimura ◽  
Wen Fu ◽  
Rania Soudy ◽  
David MacTavish ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Long Term Potentiation ◽  
Therapeutic Benefit ◽  
Plaque Burden ◽  
Amyloid Precursor Protein Gene ◽  
Amyloid Β Peptide ◽  
Class B

Abstract Based upon its interactions with amyloid β peptide (Aβ), the amylin receptor, a Class B G protein-coupled receptor (GPCR), is a potential modulator of Alzheimer’s disease (AD) pathogenesis. However, past pharmacological approaches have failed to resolve whether activation or blockade of this receptor would have greater therapeutic benefit. To address this issue, we generated compound mice expressing a human amyloid precursor protein gene with familial AD mutations in combination with deficiency of amylin receptors produced by hemizygosity for the critical calcitonin receptor subunit of this heterodimeric GPCR. These compound transgenic AD mice demonstrated attenuated responses to human amylin- and Aβ-induced depression of hippocampal long term potentiation (LTP) in keeping with the genetic depletion of amylin receptors. Both the LTP responses and spatial memory (as measured with Morris Water Maze) in these mice were improved compared to AD mouse controls and, importantly, a reduction in both the amyloid plaque burden and markers of neuroinflammation was observed. Our data support the notion of further development of antagonists of the amylin receptor as AD-modifying therapies.

Inhibitors of protein aggregation and toxicity

2009 ◽  
Vol 37 (4) ◽  
pp. 692-696 ◽  
Author(s):  
Hozefa Amijee ◽  
Jill Madine ◽  
David A. Middleton ◽  
Andrew J. Doig
Keyword(s):  
Amyloid Β ◽  
Long Term Potentiation ◽  
Amyloid Β Peptide ◽  
Recognition Element ◽  
Self Recognition ◽  
Term Potentiation ◽  
Starting Point ◽  
Aβ Amyloid ◽  
Aggregation Inhibitors ◽  
Ad Alzheimer’S Disease

The aggregation of numerous peptides or proteins has been linked to the onset of disease, including Aβ (amyloid β-peptide) in AD (Alzheimer's disease), asyn (α-synuclein) in Parkinson's disease and amylin in Type 2 diabetes. Diverse amyloidogenic proteins can often be cut down to an SRE (self-recognition element) of as few as five residues that retains the ability to aggregate. SREs can be used as a starting point for aggregation inhibitors. In particular, N-methylated SREs can bind to a target on one side, but have hydrogen-bonding blocked on their methylated face, interfering with further assembly. We applied this strategy to develop Aβ toxicity inhibitors. Our compounds, and a range of compounds from the literature, were compared under the same conditions, using biophysical and toxicity assays. Two N-methylated D-peptide inhibitors with unnatural side chains were the most effective and can reverse Aβ-induced inhibition of LTP (long-term potentiation) at concentrations as low as 10 nM. An SRE in asyn (VAQKTV) was identified using solid-state NMR. When VAQKTV was N-methylated, it was able to disrupt asyn aggregation. N-methylated derivatives of the SRE of amylin are also able to inhibit amylin aggregation.

scholarly journals Genetic Depletion of Amylin/Calcitonin Receptors Improves Memory and Learning in Transgenic Alzheimer’s Disease Mouse Models

2021 ◽  
Author(s):  
Aarti Patel ◽  
Ryoichi Kimura ◽  
Wen Fu ◽  
Rania Soudy ◽  
David MacTavish ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Long Term Potentiation ◽  
Therapeutic Benefit ◽  
Plaque Burden ◽  
Amyloid Precursor Protein Gene ◽  
Amyloid Β Peptide ◽  
Class B

AbstractBased upon its interactions with amyloid β peptide (Aβ), the amylin receptor, a class B G protein-coupled receptor (GPCR), is a potential modulator of Alzheimer’s disease (AD) pathogenesis. However, past pharmacological approaches have failed to resolve whether activation or blockade of this receptor would have greater therapeutic benefit. To address this issue, we generated compound mice expressing a human amyloid precursor protein gene with familial AD mutations in combination with deficiency of amylin receptors produced by hemizygosity for the critical calcitonin receptor subunit of this heterodimeric GPCR. These compound transgenic AD mice demonstrated attenuated responses to human amylin- and Aβ-induced depression of hippocampal long-term potentiation (LTP) in keeping with the genetic depletion of amylin receptors. Both the LTP responses and spatial memory (as measured with Morris water maze) in these mice were improved compared to AD mouse controls and, importantly, a reduction in both the amyloid plaque burden and markers of neuroinflammation was observed. Our data support the notion of further development of antagonists of the amylin receptor as AD-modifying therapies.

Neuroprotective properties of mitochondria-targeted antioxidants of the SkQ-type

2016 ◽  
Vol 27 (8) ◽  
pp. 849-855 ◽  
Author(s):  
Nickolay K. Isaev ◽  
Elena V. Stelmashook ◽  
Elisaveta E. Genrikhs ◽  
Galina A. Korshunova ◽  
Natalya V. Sumbatyan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Area ◽  
Hippocampal Slices ◽  
Amyloid Β ◽  
Long Term Potentiation ◽  
Term Potentiation ◽  
Neuroprotective Action

AbstractIn 2008, using a model of compression brain ischemia, we presented the first evidence that mitochondria-targeted antioxidants of the SkQ family, i.e. SkQR1 [10-(6′-plastoquinonyl)decylrhodamine], have a neuroprotective action. It was shown that intraperitoneal injections of SkQR1 (0.5–1 μmol/kg) 1 day before ischemia significantly decreased the damaged brain area. Later, we studied in more detail the anti-ischemic action of this antioxidant in a model of experimental focal ischemia provoked by unilateral intravascular occlusion of the middle cerebral artery. The neuroprotective action of SkQ family compounds (SkQR1, SkQ1, SkQTR1, SkQT1) was manifested through the decrease in trauma-induced neurological deficit in animals and prevention of amyloid-β-induced impairment of long-term potentiation in rat hippocampal slices. At present, most neurophysiologists suppose that long-term potentiation underlies cellular mechanisms of memory and learning. They consider inhibition of this process by amyloid-β1-42as anin vitromodel of memory disturbance in Alzheimer’s disease. Further development of the above studies revealed that mitochondria-targeted antioxidants could retard accumulation of hyperphosphorylated τ-protein, as well as amyloid-β1-42, and its precursor APP in the brain, which are involved in developing neurodegenerative processes in Alzheimer’s disease.

scholarly journals The antioxidant xanthorrhizol prevents amyloid-β-induced oxidative modification and inactivation of neprilysin

2018 ◽  
Vol 38 (1) ◽  
Author(s):  
Chol Seung Lim ◽  
Jung-Soo Han
Keyword(s):  
Therapeutic Potential ◽  
Neuroblastoma Cells ◽  
Amyloid Β ◽  
Enzymatic Activities ◽  
Oxidative Modification ◽  
Amyloid Β Peptide ◽  
Oxygen Species ◽  
Human Neuroblastoma Cells ◽  
Neuroprotective Effects ◽  
Human Neuroblastoma

Activity of neprilysin (NEP), the major protease which cleaves amyloid-β peptide (Aβ), is reportedly reduced in the brains of patients with Alzheimer’s disease (AD). Accumulation of Aβ generates reactive oxygen species (ROS) such as 4-hydroxynonenal (HNE), and then reduces activities of Aβ-degrading enzymes including NEP. Xanthorrhizol (Xan), a natural sesquiterpenoid, has been reported to possess antioxidant and anti-inflammatory properties. The present study examined the effects of Xan on HNE- or oligomeric Aβ42-induced oxidative modification of NEP protein. Xan was added to the HNE- or oligomeric Aβ42-treated SK-N-SH human neuroblastoma cells and then levels, oxidative modification and enzymatic activities of NEP protein were measured. Increased HNE levels on NEP proteins and reduced enzymatic activities of NEP were observed in the HNE- or oligomeric Aβ42-treated cells. Xan reduced HNE levels on NEP proteins and preserved enzymatic activities of NEP in HNE- or oligomeric Aβ42-treated cells. Xan reduced Aβ42 accumulation and protected neurones against oligomeric Aβ42-induced neurotoxicity through preservation of NEP activities. These findings indicate that Xan possesses therapeutic potential for the treatment of neurodegenerative diseases, including AD, and suggest a potential mechanism for the neuroprotective effects of antioxidants for the prevention of AD.

Sign in / Sign up

Export Citation Format

Share Document