An Amyloid-β Targeting Chemical Exchange Saturation Transfer Probe for In Vivo Detection of Alzheimer’s Disease

Alzheimer’s disease (AD) is one of the most common causes of dementia and difficult to study as the pool of subjects is highly heterogeneous. Saturation transfer (ST) magnetic resonance imaging (MRI) methods are quantitative modalities with potential for non-invasive identification and tracking of various aspects of AD pathology. In this review we cover ST-MRI studies in both humans and animal models of AD over the past 20 years. A number of magnetization transfer (MT) studies have shown promising results in human brain. Increased computing power enables more quantitative MT studies, while access to higher magnetic fields improves the specificity of chemical exchange saturation transfer (CEST) techniques. While much work remains to be done, results so far are very encouraging. MT is sensitive to patterns of AD-related pathological changes, improving differential diagnosis, and CEST is sensitive to particular pathological processes which could greatly assist in the development and monitoring of therapeutic treatments of this currently incurable disease.

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Early detection of Alzheimer's disease using creatine chemical exchange saturation transfer magnetic resonance imaging

NeuroImage ◽

10.1016/j.neuroimage.2021.118071 ◽

2021 ◽

Vol 236 ◽

pp. 118071

Author(s):

Lin Chen ◽

Peter C.M. van Zijl ◽

Zhiliang Wei ◽

Hanzhang Lu ◽

Wenzhen Duan ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Magnetic Resonance ◽

Early Detection ◽

Chemical Exchange ◽

Chemical Exchange Saturation Transfer ◽

Saturation Transfer ◽

Resonance Imaging

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In vitro and in vivo comparison of MRI chemical exchange saturation transfer (CEST) properties between native glucose and 3‐O‐Methyl‐D‐glucose in a murine tumor model

NMR in Biomedicine ◽

10.1002/nbm.4602 ◽

2021 ◽

Author(s):

Annasofia Anemone ◽

Martina Capozza ◽

Francesca Arena ◽

Sara Zullino ◽

Paola Bardini ◽

...

Keyword(s):

Chemical Exchange ◽

Tumor Model ◽

Chemical Exchange Saturation Transfer ◽

Saturation Transfer ◽

Murine Tumor ◽

Murine Tumor Model

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Transcranial in vivo detection of amyloid-beta at single plaque resolution with large-field multifocal illumination fluorescence microscopy

10.1101/2020.02.01.929844 ◽

2020 ◽

Cited By ~ 2

Author(s):

Ruiqing Ni ◽

Zhenyue Chen ◽

Gloria Shi ◽

Alessia Villois ◽

Quanyu Zhou ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Fluorescence Microscopy ◽

Amyloid Beta ◽

Large Field ◽

Microscopy Technique ◽

In Vivo Detection ◽

Amyloid Deposits ◽

Microscopy Techniques

AbstractThe abnormal deposition of beta-amyloid proteins in the brain is one of the major histopathological hallmarks of Alzheimer’s disease. Currently available intravital microscopy techniques for high-resolution plaque visualization commonly involve highly invasive procedures and are limited to a small field-of-view within the rodent brain. Here, we report the transcranial detection of amyloid-beta deposits at the whole brain scale with 20 μm resolution in APP/PS1 and arcAβ mouse models of Alzheimer’s disease amyloidosis using a large-field multifocal (LMI) fluorescence microscopy technique. Highly sensitive and specific detection of amyloid-beta deposits at a single plaque level in APP/PS1 and arcAβ mice was facilitated using luminescent conjugated oligothiophene HS-169. Immunohistochemical staining with HS-169, anti-Aβ antibody 6E10, and conformation antibodies OC (fibrillar) of brain tissue sections further showed that HS-169 resolved compact parenchymal and vessel-associated amyloid deposits. The novel imaging platform offers new prospects for in vivo studies into Alzheimer’s disease mechanisms in animal models as well as longitudinal monitoring of therapeutic responses at a single plaque level.

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Application of optogenetic Amyloid-β distinguishes between metabolic and physical damages in neurodegeneration

eLife ◽

10.7554/elife.52589 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 3

Author(s):

Chu Hsien Lim ◽

Prameet Kaur ◽

Emelyne Teo ◽

Vanessa Yuk Man Lam ◽

Fangchen Zhu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Disease Progression ◽

Biological Effects ◽

Amyloid Β ◽

Tissue Loss ◽

Amyloid Β Peptide ◽

Physical Damage ◽

Living Tissues

The brains of Alzheimer’s disease patients show a decrease in brain mass and a preponderance of extracellular Amyloid-β plaques. These plaques are formed by aggregation of polypeptides that are derived from the Amyloid Precursor Protein (APP). Amyloid-β plaques are thought to play either a direct or an indirect role in disease progression, however the exact role of aggregation and plaque formation in the aetiology of Alzheimer’s disease (AD) is subject to debate as the biological effects of soluble and aggregated Amyloid-β peptides are difficult to separate in vivo. To investigate the consequences of formation of Amyloid-β oligomers in living tissues, we developed a fluorescently tagged, optogenetic Amyloid-β peptide that oligomerizes rapidly in the presence of blue light. We applied this system to the crucial question of how intracellular Amyloid-β oligomers underlie the pathologies of A. We use Drosophila, C. elegans and D. rerio to show that, although both expression and induced oligomerization of Amyloid-β were detrimental to lifespan and healthspan, we were able to separate the metabolic and physical damage caused by light-induced Amyloid-β oligomerization from Amyloid-β expression alone. The physical damage caused by Amyloid-β oligomers also recapitulated the catastrophic tissue loss that is a hallmark of late AD. We show that the lifespan deficit induced by Amyloid-β oligomers was reduced with Li+ treatment. Our results present the first model to separate different aspects of disease progression.

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Elevated Expression of MiR-17 in Microglia of Alzheimer’s Disease Patients Abrogates Autophagy-Mediated Amyloid-β Degradation

Frontiers in Immunology ◽

10.3389/fimmu.2021.705581 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shady Estfanous ◽

Kylene P. Daily ◽

Mostafa Eltobgy ◽

Nicholas P. Deems ◽

Midhun N. K. Anne ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Therapeutic Interventions ◽

Tissue Sections ◽

Cargo Receptor ◽

5Xfad Mouse ◽

Aβ Degradation

Autophagy is a proposed route of amyloid-β (Aβ) clearance by microglia that is halted in Alzheimer’s Disease (AD), though mechanisms underlying this dysfunction remain elusive. Here, primary microglia from adult AD (5xFAD) mice were utilized to demonstrate that 5xFAD microglia fail to degrade Aβ and express low levels of autophagy cargo receptor NBR1. In 5xFAD mouse brains, we show for the first time that AD microglia express elevated levels of microRNA cluster Mirc1/Mir17-92a, which is known to downregulate autophagy proteins. By in situ hybridization in post-mortem AD human tissue sections, we observed that the Mirc1/Mir17-92a cluster member miR-17 is also elevated in human AD microglia, specifically in the vicinity of Aβ deposits, compared to non-disease controls. We show that NBR1 expression is negatively correlated with expression of miR-17 in human AD microglia via immunohistopathologic staining in human AD brain tissue sections. We demonstrate in healthy microglia that autophagy cargo receptor NBR1 is required for Aβ degradation. Inhibiting elevated miR-17 in 5xFAD mouse microglia improves Aβ degradation, autophagy, and NBR1 puncta formation in vitro and improves NBR1 expression in vivo. These findings offer a mechanism behind dysfunctional autophagy in AD microglia which may be useful for therapeutic interventions aiming to improve autophagy function in AD.

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