Amyloid β Peptide-Induced Changes in Prefrontal Cortex Activity and Its Response to Hippocampal Input

Alterations in prefrontal cortex (PFC) function and abnormalities in its interactions with other brain areas (i.e., the hippocampus) have been related to Alzheimer Disease (AD). Considering that these malfunctions correlate with the increase in the brain’s amyloid beta (Aβ) peptide production, here we looked for a causal relationship between these pathognomonic signs of AD. Thus, we tested whether or not Aβ affects the activity of the PFC network and the activation of this cortex by hippocampal input stimulation in vitro. We found that Aβ application to brain slices inhibits PFC spontaneous network activity as well as PFC activation, both at the population and at the single-cell level, when the hippocampal input is stimulated. Our data suggest that Aβ can contribute to AD by disrupting PFC activity and its long-range interactions throughout the brain.

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Alterations in Piriform and Bulbar Activity/Excitability/Coupling Upon Amyloid-β Administration in vivo Related to Olfactory Dysfunction

Journal of Alzheimer s Disease ◽

10.3233/jad-201392 ◽

2021 ◽

pp. 1-17

Author(s):

Ignacio Martínez-García ◽

Rebeca Hernández-Soto ◽

Benjamín Villasana-Salazar ◽

Benito Ordaz ◽

Fernando Peña-Ortega

Keyword(s):

Piriform Cortex ◽

Brain Slices ◽

Amyloid Β ◽

Olfactory Dysfunction ◽

Network Activity ◽

Pathological Changes ◽

Olfactory Pathway ◽

Lateral Olfactory Tract

Background: Deficits in odor detection and discrimination are premature symptoms of Alzheimer’s disease (AD) that correlate with pathological signs in the olfactory bulb (OB) and piriform cortex (PCx). Similar olfactory dysfunction has been characterized in AD transgenic mice that overproduce amyloid-β (Aβ), which can be prevented by reducing Aβ levels by immunological and pharmacological means, suggesting that olfactory dysfunction depends on Aβ accumulation and Aβ-driven alterations in the OB and/or PCx, as well as on their activation. However, this possibility was not directly tested before. Objective: To characterize the effects of Aβ on OB and PCx excitability/coupling and on olfaction. Methods: Aβ oligomerized solution (containing oligomers, monomers, and protofibrils) or its vehicle were intracerebroventricularlly injected two weeks before OB and PCx excitability and synchrony were evaluated through field recordings in vivo and in brain slices. Synaptic transmission from the OB to the PCx was also evaluated in vitro. Olfaction was assessed through the habituation/dishabituation test. Results: Aβ did not affect lateral olfactory tract transmission into the PCx but reduced odor habituation and cross-habituation. This olfactory dysfunction was related to a reduction of PCx and OB network activity power in vivo. Moreover, the coherence between PCx-OB activities was also reduced by Aβ. Finally, Aβ treatment exacerbated the 4-aminopyridine-induced excitation in the PCx in vitro. Conclusion: Our results show that Aβ-induced olfactory dysfunction involves a complex set of pathological changes at different levels of the olfactory pathway including alterations in PCx excitability and its coupling with the OB. These pathological changes might contribute to hyposmia in AD.

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Augmentation of Bri2 molecular chaperone activity against amyloid-β reduces neurotoxicity in mouse hippocampus in vitro

Communications Biology ◽

10.1038/s42003-020-0757-z ◽

2020 ◽

Vol 3 (1) ◽

Cited By ~ 6

Author(s):

Gefei Chen ◽

Yuniesky Andrade-Talavera ◽

Simone Tambaro ◽

Axel Leppert ◽

Harriet E. Nilsson ◽

...

Keyword(s):

Molecular Chaperone ◽

Molecular Chaperones ◽

Quaternary Structure ◽

Therapeutic Potential ◽

Amyloid Β ◽

Network Activity ◽

Amyloid Β Peptide ◽

Neuronal Network Activity ◽

Age Related

AbstractMolecular chaperones play important roles in preventing protein misfolding and its potentially harmful consequences. Deterioration of molecular chaperone systems upon ageing are thought to underlie age-related neurodegenerative diseases, and augmenting their activities could have therapeutic potential. The dementia relevant domain BRICHOS from the Bri2 protein shows qualitatively different chaperone activities depending on quaternary structure, and assembly of monomers into high-molecular weight oligomers reduces the ability to prevent neurotoxicity induced by the Alzheimer-associated amyloid-β peptide 1-42 (Aβ42). Here we design a Bri2 BRICHOS mutant (R221E) that forms stable monomers and selectively blocks a main source of toxic species during Aβ42 aggregation. Wild type Bri2 BRICHOS oligomers are partly disassembled into monomers in the presence of the R221E mutant, which leads to potentiated ability to prevent Aβ42 toxicity to neuronal network activity. These results suggest that the activity of endogenous molecular chaperones may be modulated to enhance anti-Aβ42 neurotoxic effects.

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Phenolic Acids Exert Anticholinesterase and Cognition-Improving Effects

Current Alzheimer Research ◽

10.2174/1567205014666171128102557 ◽

2018 ◽

Vol 15 (6) ◽

pp. 531-543 ◽

Cited By ~ 4

Author(s):

Dominik Szwajgier ◽

Ewa Baranowska-Wojcik ◽

Kamila Borowiec

Keyword(s):

Phenolic Acids ◽

Ex Vivo ◽

Amyloid Β ◽

Inhibitory Effect ◽

In Vivo Studies ◽

Amyloid Β Peptide ◽

Beneficial Effects ◽

Aβ Fibrils

Numerous authors have provided evidence regarding the beneficial effects of phenolic acids and their derivatives against Alzheimer's disease (AD). In this review, the role of phenolic acids as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is discussed, including the structure-activity relationship. In addition, the inhibitory effect of phenolic acids on the formation of amyloid β-peptide (Aβ) fibrils is presented. We also cover the in vitro, ex vivo, and in vivo studies concerning the prevention and treatment of the cognitive enhancement.

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In vitro biological activity of Salvia fruticosa Mill. infusion against amyloid β-peptide-induced toxicity and inhibition of GSK-3β, CK-1δ, and BACE-1 enzymes relevant to Alzheimer's disease

Saudi Pharmaceutical Journal ◽

10.1016/j.jsps.2021.01.007 ◽

2021 ◽

Vol 29 (3) ◽

pp. 236-243

Author(s):

Perihan Gürbüz ◽

Alim Hüseyin Dokumacı ◽

Miyase Gözde Gündüz ◽

Concepcion Perez ◽

Fatih Göger ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Biological Activity ◽

Amyloid Β ◽

Amyloid Β Peptide ◽

Salvia Fruticosa ◽

Gsk 3Β ◽

Bace 1

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Repeated electromagnetic field stimulation lowers amyloid-β peptide levels in primary human mixed brain tissue cultures

Scientific Reports ◽

10.1038/s41598-020-77808-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Felipe P. Perez ◽

Bryan Maloney ◽

Nipun Chopra ◽

Jorge J. Morisaki ◽

Debomoy K. Lahiri

Keyword(s):

Electromagnetic Field ◽

Late Onset ◽

Amyloid Β ◽

Clinical Settings ◽

Amyloid Β Peptide ◽

Field Stimulation ◽

Amino Acid Residues ◽

Hyperphosphorylated Tau Protein ◽

Magnetic Resonance Imaging Mri

AbstractLate Onset Alzheimer’s Disease is the most common cause of dementia, characterized by extracellular deposition of plaques primarily of amyloid-β (Aβ) peptide and tangles primarily of hyperphosphorylated tau protein. We present data to suggest a noninvasive strategy to decrease potentially toxic Aβ levels, using repeated electromagnetic field stimulation (REMFS) in primary human brain (PHB) cultures. We examined effects of REMFS on Aβ levels (Aβ40 and Aβ42, that are 40 or 42 amino acid residues in length, respectively) in PHB cultures at different frequencies, powers, and specific absorption rates (SAR). PHB cultures at day in vitro 7 (DIV7) treated with 64 MHz, and 1 hour daily for 14 days (DIV 21) had significantly reduced levels of secreted Aβ40 (p = 001) and Aβ42 (p = 0.029) peptides, compared to untreated cultures. PHB cultures (DIV7) treated at 64 MHz, for 1 or 2 hour during 14 days also produced significantly lower Aβ levels. PHB cultures (DIV28) treated with 64 MHz 1 hour/day during 4 or 8 days produced a similar significant reduction in Aβ40 levels. 0.4 W/kg was the minimum SAR required to produce a biological effect. Exposure did not result in cellular toxicity nor significant changes in secreted Aβ precursor protein-α (sAPPα) levels, suggesting the decrease in Aβ did not likely result from redirection toward the α-secretase pathway. EMF frequency and power used in our work is utilized in human magnetic resonance imaging (MRI, thus suggesting REMFS can be further developed in clinical settings to modulate Aβ deposition.

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P-Glycoprotein and Breast Cancer Resistance Protein Restrict Apical-to-Basolateral Permeability of Human Brain Endothelium to Amyloid-β

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2009.42 ◽

2009 ◽

Vol 29 (6) ◽

pp. 1079-1083 ◽

Cited By ~ 73

Author(s):

Leon M Tai ◽

A Jane Loughlin ◽

David K Male ◽

Ignacio A Romero

Keyword(s):

Breast Cancer ◽

Human Brain ◽

Breast Cancer Resistance Protein ◽

Amyloid Β ◽

Cancer Resistance ◽

Glycoprotein P ◽

P Glycoprotein ◽

Resistance Protein ◽

The Brain

The clearance of amyloid beta (Aβ) from the brain represents a novel therapeutic target for Alzheimer's disease. Conflicting data exist regarding the contribution of adenosine triphosphatebinding cassette transporters to the clearance of Aβ through the blood-brain barrier. Therefore, we investigated whether Aβ could be a substrate for P-glycoprotein (P-gp) and/or for breast cancer resistance protein (BCRP) using a human brain endothelial cell line, hCMEC/D3. Inhibition of P-gp and BCRP increased apical-to-basolateral, but not basolateral-to-apical, permeability of hCMEC/D3 cells to 125l Aβ 1–40. Our in vitro data suggest that P-gp and BCRP might act to prevent the blood-borne Aβ 1–40 from entering the brain.

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TMOD-31. AN ORGANOTYPIC TISSUE PLATFORM TO BRIDGE IN VITRO AND IN VIVO ASSAYS FOR BRAIN CANCER TREATMENT

Neuro-Oncology ◽

10.1093/neuonc/noab196.892 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi222-vi222

Author(s):

Breanna Mann ◽

Noah Bell ◽

Denise Dunn ◽

Scott Floyd ◽

Shawn Hingtgen ◽

...

Keyword(s):

Cell Lines ◽

Brain Cancer ◽

Brain Slice ◽

Brain Slices ◽

In Vitro Assays ◽

Preclinical Model ◽

Short Period ◽

The Brain

Abstract Brain cancers remain one of the greatest medical challenges. The lack of experimentally tractable models that recapitulate brain structure/function represents a major impediment. Platforms that enable functional testing in high-fidelity models are urgently needed to accelerate the identification and translation of therapies to improve outcomes for patients suffering from brain cancer. In vitro assays are often too simple and artificial while in vivo studies can be time-intensive and complicated. Our live, organotypic brain slice platform can be used to seed and grow brain cancer cell lines, allowing us to bridge the existing gap in models. These tumors can rapidly establish within the brain slice microenvironment, and morphologic features of the tumor can be seen within a short period of time. The growth, migration, and treatment dynamics of tumors seen on the slices recapitulate what is observed in vivo yet is missed by in vitro models. Additionally, the brain slice platform allows for the dual seeding of different cell lines to simulate characteristics of heterogeneous tumors. Furthermore, live brain slices with embedded tumor can be generated from tumor-bearing mice. This method allows us to quantify tumor burden more effectively and allows for treatment and retreatment of the slices to understand treatment response and resistance that may occur in vivo. This brain slice platform lays the groundwork for a new clinically relevant preclinical model which provides physiologically relevant answers in a short amount of time leading to an acceleration of therapeutic translation.

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The metabolism of polyphosphoinositides in hen brain and sciatic nerve

Biochemical Journal ◽

10.1042/bj1110157 ◽

1969 ◽

Vol 111 (2) ◽

pp. 157-165 ◽

Cited By ~ 23

Author(s):

A. Sheltawy ◽

R. M. C. Dawson

Keyword(s):

Sciatic Nerve ◽

Previous Investigation ◽

Relative Rate ◽

Specific Radioactivity ◽

Brain Slices ◽

Soluble Phosphorus ◽

Ethanolamine Plasmalogen ◽

32P Incorporation ◽

The Brain

1. The distribution of individual phospholipids was determined in hen brain and compared with that in sciatic nerve obtained in a previous investigation. Sciatic nerve is more enriched in the myelinic phospholipids ethanolamine plasmalogen, phosphatidylserine and sphingomyelin, but it contains relatively less triphosphoinositide, and much less diphosphoinositide, than the brain. 2. The course of incorporation of intraperitoneally injected 32P into the acid-soluble phosphorus, phosphoinositides and total phospholipids of hen brain and sciatic nerve was followed. Although the maximum specific radioactivity in sciatic nerve of acid-soluble phosphorus is 4·5 times, and that of triphosphoinositide six times, that in the brain, the relative rate of triphosphoinositide phosphorus synthesis per gram of brain is three times that in sciatic nerve. 3. Administration of the demyelinating agent tri-o-cresyl phosphate to hens has no significant effect on the amounts or the rate of 32P incorporation into the total phospholipids of the sciatic nerve. However, the rate of incorporation of 32P into triphosphoinositide, although not its concentration, is raised from the first day after administration of the drug and remains thus 13 and 23 days later. 4. The incorporation of 32P into polyphosphoinositides of hen brain slices in vitro was studied. The recovery of triphosphoinositide from the slices is markedly increased in the presence of EDTA, although the rate of incorporation of 32P is unaffected. The incorporation of 32P is dependent on the presence of Mg2+ and Ca2+ in the medium, and is decreased when Na+ is replaced with K+ or cholinium ions.

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LongShengZhi Capsule Attenuates Alzheimer-Like Pathology in APP/PS1 Double Transgenic Mice by Reducing Neuronal Oxidative Stress and Inflammation

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2020.582455 ◽

2020 ◽

Vol 12 ◽

Author(s):

Zequn Yin ◽

Xuerui Wang ◽

Shihong Zheng ◽

Peichang Cao ◽

Yuanli Chen ◽

...

Keyword(s):

Oxidative Stress ◽

Transgenic Mice ◽

Amyloid Β ◽

B Cell Lymphoma ◽

Acanthopanax Senticosus ◽

Neuroprotective Effects ◽

Long Term Treatment ◽

Double Transgenic Mice ◽

The Brain

Alzheimer’s disease (AD) is the most common form of dementia in the elderly. It may be caused by oxidative stress, inflammation, and cerebrovascular dysfunctions in the brain. LongShengZhi Capsule (LSZ), a traditional Chinese medicine, has been approved by the China Food and Drug Administration for treatment of patients with cardiovascular/cerebrovascular disease. LSZ contains several neuroprotective ingredients, including Hirudo, Astmgali Radix, Carthami Flos (Honghua), Persicae Semen (Taoren), Acori Tatarinowii Rhizoma (Shichangpu), and Acanthopanax Senticosus (Ciwujia). In this study, we aimed to determine the effect of LSZ on the AD process. Double transgenic mice expressing the amyloid-β precursor protein and mutant human presenilin 1 (APP/PS1) to model AD were treated with LSZ for 7 months starting at 2 months of age. LSZ significantly improved the cognition of the mice without adverse effects, indicating its high degree of safety and efficacy after a long-term treatment. LSZ reduced AD biomarker Aβ plaque accumulation by inhibiting β-secretase and γ-secretase gene expression. LSZ also reduced p-Tau expression, cell death, and inflammation in the brain. Consistently, in vitro, LSZ ethanol extract enhanced neuronal viability by reducing L-glutamic acid-induced oxidative stress and inflammation in HT-22 cells. LSZ exerted antioxidative effects by enhancing superoxide dismutase and glutathione peroxidase expression, reduced Aβ accumulation by inhibiting β-secretase and γ-secretase mRNA expression, and decreased p-Tau level by inhibiting NF-κB-mediated inflammation. It also demonstrated neuroprotective effects by regulating the Fas cell surface death receptor/B-cell lymphoma 2/p53 pathway. Taken together, our study demonstrates the antioxidative stress, anti-inflammatory, and neuroprotective effects of LSZ in the AD-like pathological process and suggests it could be a potential medicine for AD treatment.

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