Proton Stimulation Targeting Plaque Magnetite Reduces Amyloid-β Plaque and Iron Redox Toxicity and Improves Memory in an Alzheimer’s Disease Mouse Model

Background: The coexistence of magnetite within protein aggregates in the brain is a typical pathologic feature of Alzheimer’s disease (AD), and the formation of amyloid-β (Aβ) plaques induces critical impairment of cognitive function. Objective: This study aimed to investigate the therapeutic effect of proton stimulation (PS) targeting plaque magnetite in the transgenic AD mouse brain. Methods: A proton transmission beam was applied to the whole mouse brain at a single entrance dose of 2 or 4 Gy to test the effect of disruption of magnetite-containing Aβ plaques by electron emission from magnetite. The reduction in Aβ plaque burden and the cognitive function of the PS-treated mouse group were assayed by histochemical analysis and memory tests, respectively. Aβ-magnetite and Aβ fibrils were treated with PS to investigate the breakdown of the amyloid protein matrix. Results: Single PS induced a 48–87%reduction in both the amyloid plaque burden and ferrous-containing magnetite level in the early-onset AD mouse brain while saving normal tissue. The overall Aβ plaque burden (68–82%) and (94–97%) hippocampal magnetite levels were reduced in late onset AD mice that showed improvements in cognitive function after PS compared with untreated AD mice (p < 0.001). Analysis of amyloid fibrils after exposure to a single 2 or 4 Gy proton transmission beam demonstrated that the protein matrix was broken down only in magnetite-associated Aβ fibrils. Conclusion: Single PS targeting plaque magnetite effectively decreases the amyloid plaque burden and the ferrous-containing magnetite level, and this effect is useful for memory recovery.

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Immunization with the SDPM1 peptide lowers amyloid plaque burden and improves cognitive function in the APPswePSEN1(A246E) transgenic mouse model of Alzheimer's disease

Neurobiology of Disease ◽

10.1016/j.nbd.2010.05.013 ◽

2010 ◽

Vol 39 (3) ◽

pp. 409-422 ◽

Cited By ~ 6

Author(s):

Chiou-Miin Wang ◽

Sarah deVries ◽

Marybeth Camboni ◽

Matthew Glass ◽

Paul T. Martin

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Function ◽

Mouse Model ◽

Transgenic Mouse ◽

Amyloid Plaque ◽

Transgenic Mouse Model ◽

Plaque Burden ◽

Model Of Alzheimer’S Disease

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

10.21203/rs.3.rs-515476/v1 ◽

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.

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Reduction of Amyloid Burden by Proliferated Homeostatic Microglia in Toxoplasma gondii-Infected Alzheimer’s Disease Model Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22052764 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2764

Author(s):

Ji-Hun Shin ◽

Young Sang Hwang ◽

Bong-Kwang Jung ◽

Seung-Hwan Seo ◽

Do-Won Ham ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Toxoplasma Gondii ◽

Disease Model ◽

Amyloid Β ◽

Amyloid Plaque ◽

Plaque Burden ◽

Microglial Phagocytosis ◽

Microglial Proliferation ◽

Toxoplasma Gondii Infection

In this study, we confirmed that the number of resident homeostatic microglia increases during chronic Toxoplasma gondii infection. Given that the progression of Alzheimer’s disease (AD) worsens with the accumulation of amyloid β (Aβ) plaques, which are eliminated through microglial phagocytosis, we hypothesized that T. gondii-induced microglial proliferation would reduce AD progression. Therefore, we investigated the association between microglial proliferation and Aβ plaque burden using brain tissues isolated from 5XFAD AD mice (AD group) and T. gondii-infected AD mice (AD + Toxo group). In the AD + Toxo group, amyloid plaque burden significantly decreased compared with the AD group; conversely, homeostatic microglial proliferation, and number of plaque-associated microglia significantly increased. As most plaque-associated microglia shifted to the disease-associated microglia (DAM) phenotype in both AD and AD + Toxo groups and underwent apoptosis after the lysosomal degradation of phagocytosed Aβ plaques, this indicates that a sustained supply of homeostatic microglia is required for alleviating Aβ plaque burden. Thus, chronic T. gondii infection can induce microglial proliferation in the brains of mice with progressed AD; a sustained supply of homeostatic microglia is a promising prospect for AD treatment.

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

Molecular Neurobiology ◽

10.1007/s12035-021-02490-y ◽

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.

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Silymarin Attenuated the Amyloid β Plaque Burden and Improved Behavioral Abnormalities in an Alzheimer’s Disease Mouse Model

Bioscience Biotechnology and Biochemistry ◽

10.1271/bbb.100524 ◽

2010 ◽

Vol 74 (11) ◽

pp. 2299-2306 ◽

Cited By ~ 42

Author(s):

Nakaba MURATA ◽

Kazuma MURAKAMI ◽

Yusuke OZAWA ◽

Noriaki KINOSHITA ◽

Kazuhiro IRIE ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Amyloid Β ◽

Plaque Burden ◽

Behavioral Abnormalities

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Microglial-associated responses to comorbid amyloid pathology and hyperhomocysteinemia in an aged knock-in mouse model of Alzheimer’s disease

Journal of Neuroinflammation ◽

10.1186/s12974-020-01938-7 ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

David J. Braun ◽

Edgardo Dimayuga ◽

Josh M. Morganti ◽

Linda J. Van Eldik

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Inflammatory Responses ◽

Specific Effect ◽

Amyloid Plaque ◽

Plaque Burden ◽

Amyloid Pathology ◽

Model Of Alzheimer’S Disease ◽

B Vitamin

Abstract Background Elevated blood homocysteine levels, termed hyperhomocysteinemia (HHcy), is a prevalent risk factor for Alzheimer’s disease (AD) in elderly populations. While dietary supplementation of B-vitamins is a generally effective method to lower homocysteine levels, there is little if any benefit to cognition. In the context of amyloid pathology, dietary-induced HHcy is known to enhance amyloid deposition and certain inflammatory responses. Little is known, however, about whether there is a more specific effect on microglia resulting from combined amyloid and HHcy pathologies. Methods The present study used a knock-in mouse model of amyloidosis, aged to 12 months, given 8 weeks of B-vitamin deficiency-induced HHcy to better understand how microglia are affected in this comorbidity context. Results We found that HHcy-inducing diet increased amyloid plaque burden, altered the neuroinflammatory milieu, and upregulated the expression of multiple damage-associated and “homeostatic” microglial genes. Conclusions Taken together, these data indicate complex effects of comorbid pathologies on microglial function that are not driven solely by increased amyloid burden. Given the highly dynamic nature of microglia, their central role in AD pathology, and the frequent occurrence of various comorbidities in AD patients, it is increasingly important to understand how microglia respond to mixed pathological processes.

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Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer’s disease: a PET substudy interim analysis

Alzheimer s Research & Therapy ◽

10.1186/s13195-019-0559-z ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 14

Author(s):

Gregory Klein ◽

Paul Delmar ◽

Nicola Voyle ◽

Sunita Rehal ◽

Carsten Hofmann ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Interim Analysis ◽

Human Monoclonal Antibody ◽

Amyloid Β ◽

Plaque Burden ◽

Ratio Method ◽

Double Blind ◽

Link Type ◽

Potential Clinical Benefit

Abstract Background We previously investigated low doses (105 or 225 mg) of gantenerumab, a fully human monoclonal antibody that binds and removes aggregated amyloid-β by Fc receptor-mediated phagocytosis, in the SCarlet RoAD (SR) and Marguerite RoAD (MR) phase 3 trials. Several lines of evidence suggested that higher doses may be necessary to achieve clinical efficacy. We therefore designed a positron emission tomography (PET) substudy to evaluate the effect of gantenerumab uptitrated to 1200 mg every 4 weeks on amyloid-β plaques as measured using florbetapir PET in patients with prodromal to moderate Alzheimer’s disease (AD). Methods A subset of patients enrolled in the SR and MR studies who subsequently entered the open-label extensions (OLEs) were included in this substudy. Patients were aged 50 to 90 years with a clinical diagnosis of probable prodromal to moderate AD and were included based on a visual read of the original screening scan in the double-blind phase. Patients were assigned to 1 of 5 titration schedules (ranging from 2 to 10 months) with a target gantenerumab dose of 1200 mg every 4 weeks. The main endpoint of this substudy was change in amyloid-β plaque burden from OLE baseline to week 52 and week 104, assessed using florbetapir PET. Florbetapir global cortical signal was calculated using a prespecified standard uptake value ratio method converted to the Centiloid scale. Results Sixty-seven of the 89 patients initially enrolled had ≥ 1 follow-up scan by August 15, 2018. Mean amyloid levels were reduced by 39 Centiloids by the first year and 59 Centiloids by year 2, a 3.5-times greater reduction than was seen after 2 years at 225 mg in SR. At years 1 and 2, 37% and 51% of patients, respectively, had amyloid-β plaque levels below the amyloid-β positivity threshold. Conclusion Results from this exploratory interim analysis of the PET substudy suggest that gantenerumab doses up to 1200 mg resulted in robust amyloid-β plaque removal at 2 years. PET amyloid levels were consistent with sparse-to-no neuritic amyloid-β plaques in 51% of patients after 2 years of therapy. Amyloid reductions were similar to those observed in other placebo-controlled studies that have suggested potential clinical benefit. Trial registration ClinicalTrials.gov, NCT01224106 (SCarlet RoAD) and NCT02051608 (Marguerite RoAD).

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Regional differences in Alzheimer’s disease pathology confound behavioural rescue after amyloid-β attenuation

Brain ◽

10.1093/brain/awz371 ◽

2019 ◽

Vol 143 (1) ◽

pp. 359-373 ◽

Cited By ~ 5

Author(s):

Christopher D Morrone ◽

Paolo Bazzigaluppi ◽

Tina L Beckett ◽

Mary E Hill ◽

Margaret M Koletar ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Cognitive Function ◽

Spatial Memory ◽

Regional Differences ◽

Amyloid Β ◽

Amyloid Β Peptide ◽

Barnes Maze ◽

Tau Pathology

Abstract Failure of Alzheimer’s disease clinical trials to improve or stabilize cognition has led to the need for a better understanding of the driving forces behind cognitive decline in the presence of active disease processes. To dissect contributions of individual pathologies to cognitive function, we used the TgF344-AD rat model, which recapitulates the salient hallmarks of Alzheimer’s disease pathology observed in patient populations (amyloid, tau inclusions, frank neuronal loss, and cognitive deficits). scyllo-Inositol treatment attenuated amyloid-β peptide in disease-bearing TgF344-AD rats, which rescued pattern separation in the novel object recognition task and executive function in the reversal learning phase of the Barnes maze. Interestingly, neither activities of daily living in the burrowing task nor spatial memory in the Barnes maze were rescued by attenuating amyloid-β peptide. To understand the pathological correlates leading to behavioural rescue, we examined the neuropathology and in vivo electrophysiological signature of the hippocampus. Amyloid-β peptide attenuation reduced hippocampal tau pathology and rescued adult hippocampal neurogenesis and neuronal function, via improvements in cross-frequency coupling between theta and gamma bands. To investigate mechanisms underlying the persistence of spatial memory deficits, we next examined neuropathology in the entorhinal cortex, a region whose input to the hippocampus is required for spatial memory. Reduction of amyloid-β peptide in the entorhinal cortex had no effect on entorhinal tau pathology or entorhinal-hippocampal neuronal network dysfunction, as measured by an impairment in hippocampal response to entorhinal stimulation. Thus, rescue or not of cognitive function is dependent on regional differences of amyloid-β, tau and neuronal network dysfunction, demonstrating the importance of staging disease in patients prior to enrolment in clinical trials. These results further emphasize the need for combination therapeutic approaches across disease progression.

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Research Progress of Alzheimer’s Disease Therapeutic Drugs: Based on Renin-Angiotensin System Axis

Journal of Alzheimer s Disease ◽

10.3233/jad-200770 ◽

2020 ◽

Vol 78 (4) ◽

pp. 1315-1338

Author(s):

Xinquan Li ◽

Weiting Xuan ◽

Dabao Chen ◽

Huawu Gao ◽

Guangyun Wang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Function ◽

Amyloid Β ◽

Renin Angiotensin System ◽

Research Progress ◽

Signal Peptides ◽

Amyloid Β Protein ◽

Angiotensin System ◽

Renin Angiotensin

It is widely recognized that Alzheimer’s disease (AD) has a complicate link to renin-angiotensin system (RAS). It is known that cerebrovascular disease has some connections with AD, but most of the studies are still conducted in parallel or independently. Although previous research came up with large number of hypotheses about the pathogenesis of AD, it does not include the mechanism of RAS-related regulation of AD. It has been found that many components of RAS have been changed in AD. For example, the multifunctional and high-efficiency vasoconstrictor Ang II and Ang III with similar effects are changed under the action of other RAS signal peptides; these signal peptides are believed to help improve nerve injury and cognitive function. These changes may lead to neuropathological changes of AD, and progressive defects of cognitive function, which are association with some hypotheses of AD. The role of RAS in AD gradually attracts our attention, and RAS deserved to be considered carefully in the pathogenesis of AD. This review discusses the mechanisms of RAS participating in the three current hypotheses of AD: neuroinflammation, oxidative stress and amyloid-β protein (Aβ) hypothesis, as well as the drugs that regulate RAS systems already in clinical or in clinical trials. It further demonstrates the importance of RAS in the pathogenesis of AD, not only because of its multiple aspects of participation, which may be accidental, but also because of the availability of RAS drugs, which can be reused as therapies of AD.

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