Loss of GPR3 reduces the amyloid plaque burden and improves memory in Alzheimer’s disease mouse models

2015 ◽  
Vol 7 (309) ◽  
pp. 309ra164-309ra164 ◽  
Author(s):  
Yunhong Huang ◽  
Aneta Skwarek-Maruszewska ◽  
Katrien Horré ◽  
Elke Vandewyer ◽  
Leen Wolfs ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Amyloid Plaque ◽  
Plaque Burden

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

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.

scholarly journals Regulation of cell distancing in peri-plaque glial nets by Plexin-B1 affects glial activation and amyloid compaction in Alzheimer’s disease

2021 ◽  
Author(s):  
Roland Friedel ◽  
Yong Huang ◽  
Minghui Wang ◽  
Shalaka Wahane ◽  
Mitzy Ríos de Anda ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Amyloid Plaque ◽  
Reactive Astrocytes ◽  
Glial Activation ◽  
Plaque Burden ◽  
Aβ Amyloid ◽  
Underlying Mechanisms

Abstract Communication between glial cells has a profound effect on the pathophysiology of Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. Here, we reveal a role of reactive astrocytes in enforcing cell distancing in the glial nets surrounding amyloid plaques, which restricts microglial coverage of Aβ, a prerequisite to detect and engulf amyloid deposits. This process is mediated through guidance receptor Plexin-B1, which we identified as a key network regulator of late-onset AD. We show that Plexin-B1 is robustly upregulated in plaque-associated astrocytes in a corona-like pattern, and its expression levels correlate with plaque burden and disease severity in AD patients. In APP/PS1 mice, an amyloidogenic model of AD, removing Plexin-B1 led to smaller peri-plaque glial nets with relaxed cell distancing and enhanced glial coverage of Aβ plaques, as well as transcriptional changes in both reactive astrocytes and disease-associated microglia that are linked to glial activation and amyloid clearance. Furthermore, amyloid plaque burden was lowered, together with a shift towards dense-core plaques and reduced neuritic dystrophy. Our data thus support a role of Plexin-B1 in controlling glial net structure by imposing cell distancing, leading to poor glial coverage of Aβ, reduced amyloid clearance and compaction. Relaxing cell distancing by targeting guidance receptors may present an alternative strategy to alleviate neuroinflammation in AD by improving glial coverage of Aβ amyloid and plaque compaction.

scholarly journals Peptide Interference with APP and Tau Association: Relevance to Alzheimer’s Disease Amelioration

2020 ◽  
Vol 21 (9) ◽  
pp. 3270
Author(s):  
Ruth Maron ◽  
Gad Armony ◽  
Michael Tsoory ◽  
Meir Wilchek ◽  
Dan Frenkel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Model ◽  
Amyloid Plaque ◽  
In Vivo Studies ◽  
Nasal Administration ◽  
Plaque Burden ◽  
Cognitive Deficiency ◽  
The Brain

The two major proteins involved in Alzheimer’s disease (AD) are the amyloid precursor protein (APP) and Tau. Here, we demonstrate that these two proteins can bind to each other. Four possible peptides APP1 (390–412), APP2 (713–730), Tau1 (19–34) and Tau2 (331–348), were predicted to be involved in this interaction, with actual binding confirmed for APP1 and Tau1. In vivo studies were performed in an Alzheimer Disease animal model—APP double transgenic (Tg) 5xFAD—as well as in 5xFAD crossed with Tau transgenic 5xFADXTau (FT), which exhibit declined cognitive reduction at four months of age. Nasal administration of APP1 and Tau1 mixture, three times a week for four or five months, reduced amyloid plaque burden as well as the level of soluble Aβ 1–42 in the brain. The treatment prevented the deterioration of cognitive functions when initiated at the age of three months, before cognitive deficiency was evident, and also at the age of six months, when such deficiencies are already observed, leading to a full regain of cognitive function.

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

2021 ◽  
pp. 1-16
Author(s):  
Seung-Jun Seo ◽  
Won-Seok Chang ◽  
Jae-Geun Jeon ◽  
Younshick Choi ◽  
EunHo Kim ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Function ◽  
Mouse Brain ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Plaque Burden ◽  
Protein Matrix ◽  
Entrance Dose ◽  
Aβ Fibrils

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.

Noradrenaline deficiency in brain increases β-amyloid plaque burden in an animal model of Alzheimer's disease

2007 ◽  
Vol 28 (8) ◽  
pp. 1206-1214 ◽  
Author(s):  
Sergey Kalinin ◽  
Vitaliy Gavrilyuk ◽  
Paul E. Polak ◽  
Robert Vasser ◽  
Jie Zhao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Model ◽  
Amyloid Plaque ◽  
Plaque Burden ◽  
Model Of Alzheimer’S Disease ◽  
Β Amyloid

P4-372 PTI-0038 causes a marked clearance of amyloid plaque burden and improved memory in a transgenic mouse model of Alzheimer's disease

2004 ◽  
Vol 25 ◽  
pp. S581
Author(s):  
Alan D. Snow ◽  
Joel A. Cummings ◽  
Beth P. Nguyen ◽  
Gerardo M. Castillo ◽  
Paula Y. Choi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Amyloid Plaque ◽  
Transgenic Mouse Model ◽  
Plaque Burden ◽  
Model Of Alzheimer’S Disease

CONTRAST-ENHANCED MR MICROSCOPY OF AMYLOID PLAQUES IN FIVE MOUSE MODELS OF ALZHEIMER'S DISEASE: COMPARISON WITH AMYLOID PLAQUE DETECTION IN HUMAN BRAINS

2017 ◽  
Vol 13 (7) ◽  
pp. P920-P921
Author(s):  
Clémence Dudeffant ◽  
Matthias Vandesquille ◽  
Marc Dhenain ◽  
Sandro Alves ◽  
Emmanuel Comoy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Amyloid Plaques ◽  
Amyloid Plaque ◽  
Mr Microscopy ◽  
Contrast Enhanced ◽  
Human Brains ◽  
Plaque Detection

scholarly journals Gene therapy for Alzheimer’s disease targeting CD33 reduces amyloid beta accumulation and neuroinflammation

2020 ◽  
Vol 29 (17) ◽  
pp. 2920-2935
Author(s):  
Ana Griciuc ◽  
Anthony N Federico ◽  
Jeyashree Natasan ◽  
Angela M Forte ◽  
Danielle McGinty ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gene Therapy ◽  
Amyloid Beta ◽  
Amyloid Plaque ◽  
Microglial Cells ◽  
Plaque Burden ◽  
Adeno Associated Virus ◽  
Gene Therapy Approach ◽  
Therapy Strategy

Abstract Neuroinflammation is a key contributor to the pathology of Alzheimer’s disease (AD). CD33 (Siglec-3) is a transmembrane sialic acid-binding receptor on the surface of microglial cells. CD33 is upregulated on microglial cells from post-mortem AD patient brains, and high levels of CD33 inhibit uptake and clearance of amyloid beta (Aβ) in microglial cell cultures. Furthermore, knockout of CD33 reduces amyloid plaque burden in mouse models of AD. Here, we tested whether a gene therapy strategy to reduce CD33 on microglia in AD could decrease Aβ plaque load. Intracerebroventricular injection of an adeno-associated virus (AAV) vector-based system encoding an artificial microRNA targeting CD33 (miRCD33) into APP/PS1 mice reduced CD33 mRNA and TBS-soluble Aβ40 and Aβ42 levels in brain extracts. Treatment of APP/PS1 mice with miRCD33 vector at an early age (2 months) was more effective at reducing Aβ plaque burden than intervening at later times (8 months). Furthermore, early intervention downregulated several microglial receptor transcripts (e.g. CD11c, CD47 and CD36) and pro-inflammatory activation genes (e.g. Tlr4 and Il1b). Marked reductions in the chemokine Ccl2 and the pro-inflammatory cytokine Tnfα were observed at the protein level in the brain of APP/PS1 mice treated with miRCD33 vector. Overall, our data indicate that CD33 is a viable target for AAV-based knockdown strategies to reduce AD pathology. One Sentence Summary: A gene therapy approach for Alzheimer’s disease using adeno-associated virus vector-based knockdown of CD33 reduced amyloid beta accumulation and neuroinflammation.

Sign in / Sign up

Export Citation Format

Share Document