Recent progress in the development of metal complexes as β-amyloid imaging probes in the brain

ABSTRACTMolecular neuroimaging techniques such as PET are proving valuable in the early and differential diagnosis of Alzheimer's disease (AD). With the advent of new therapeutic strategies aimed at reducing β-amyloid (Aβ) burden in the brain to potentially prevent or delay functional and irreversible cognitive loss, there is increased interest in developing agents that allow assessment of Aβ burden in vivo.Amyloid imaging with PET has proven useful in the discrimination of dementias, showing significantly higher Aβ burden in the gray matter of AD patients when compared with healthy controls or patients with frontotemporal dementia. ApoE ɛ4 carriers, independent of diagnosis or disease severity, present with higher Aβ burden than non-ɛ4 carriers. Amyloid imaging matches histopathological reports in aging and dementia, reflecting the true regional density of Aβ plaques in cortical areas. It also appears to be more sensitive than FDG-PET for the diagnosis of AD.In healthy older people there is an increasing prevalence of amyloid positive scans with age, rising from 20% in the seventh decade to 60% in the ninth decade. Of people with mild cognitive impairment (MCI), 40–60% present with detectable cortical Aβ deposition. In both groups, Aβ deposition is associated with a higher risk for cognitive decline and dementia due to AD. These observations suggest that Aβ deposition is not part of normal aging, supporting the hypothesis that it occurs well before the onset of symptoms and is likely to represent preclinical AD in asymptomatic persons and prodromal AD in MCI. Further longitudinal observations, coupled with different disease-specific tracers and biomarkers, are required to confirm this hypothesis and further elucidate the precise role of Aβ deposition in the course of AD.

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Measurement of β-amyloid (Aβ) clearance from the brain using metabolic labeling to diagnose Alzheimer's disease (AD)

Science-Business eXchange ◽

10.1038/scibx.2011.22 ◽

2011 ◽

Vol 4 (1) ◽

pp. 22-22

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Metabolic Labeling ◽

Amyloid Aβ ◽

Β Amyloid ◽

Aβ Clearance ◽

The Brain

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( R )- and ( S )- 18 F-labeled 2-arylbenzofurans with improved pharmacokinetics as β -amyloid imaging probes

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2017.03.073 ◽

2017 ◽

Vol 134 ◽

pp. 271-280 ◽

Cited By ~ 1

Author(s):

Jia Song ◽

Xiaoyang Zhang ◽

Yunling Zhao ◽

Hui Yang ◽

Jinming Zhang ◽

...

Keyword(s):

Amyloid Imaging ◽

Imaging Probes ◽

Β Amyloid

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Recent advances in molecular imaging probes for β-amyloid plaques

MedChemComm ◽

10.1039/c4md00365a ◽

2015 ◽

Vol 6 (3) ◽

pp. 391-402 ◽

Cited By ~ 36

Author(s):

Masahiro Ono ◽

Hideo Saji

Keyword(s):

Molecular Imaging ◽

Optical Imaging ◽

Amyloid Plaques ◽

Recent Advances ◽

Molecular Imaging Probes ◽

Imaging Probes ◽

Β Amyloid ◽

The Brain

We review recent advances in our development of molecular imaging probes for PET, SPECT, and optical imaging for in vivo detection of β-amyloid plaques in the brain.

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The Effect of the APOE4 Gene on Accumulation of Aβ 40 After Brain Injury Cannot Be Reversed by Increasing apoE4 Protein

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlw049 ◽

2016 ◽

Vol 75 (8) ◽

pp. 770-778 ◽

Cited By ~ 5

Author(s):

Patricia M. Washington ◽

Mark P. Burns

Keyword(s):

Brain Injury ◽

Amyloid Precursor Protein Processing ◽

Biphasic Response ◽

Protein Levels ◽

Abnormal Accumulation ◽

Apoe Protein ◽

Rapid Clearance ◽

Amyloid Aβ ◽

Β Amyloid ◽

The Brain

Abstract The apolipoprotein E (apoE) protein is involved in clearance of β-amyloid (Aβ) from the brain; and the APOE4 gene is associated with Aβ plaque formation in humans following traumatic brain injury (TBI). Here, we examined the association between apoE and Aβ 40 after experimental TBI and the effects of APOE alleles on this relationship. We report a biphasic response of soluble apoE protein after TBI with an acute reduction at 1 day postinjury followed by an increase at 7 days postinjury. TBI-induced Aβ 40 levels decreased as soluble apoE levels increased. In APOE4 mice there was a diminished apoE response to TBI that corresponded to prolonged accumulation of TBI-induced Aβ 40 versus that in APOE3 mice. Amyloid precursor protein processing was similar in APOE3 and APOE4 mice suggesting that impaired clearance was responsible for the abnormal accumulation of Aβ 40 in the latter. Treatment of APOE4 mice with bexarotene for 7 days increased apoE4 protein levels but was not sufficient to reduce TBI-induced Aβ 40 . Thus, rapid clearance of TBI-induced Aβ 40 occurs in mice but these pathways are impaired in APOE4 carriers. These data may help explain the deposition of Aβ in APOE4 carriers and the increased incidence of brain Aβ plaques following TBI.

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Editorial for the Genetics of Alzheimer’s Disease Special Issue: October 2021

Genes ◽

10.3390/genes12111794 ◽

2021 ◽

Vol 12 (11) ◽

pp. 1794

Author(s):

Laura Ibanez ◽

Justin B. Miller

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gray Matter ◽

Neuronal Death ◽

Tau Proteins ◽

Special Issue ◽

Amyloid Aβ ◽

Β Amyloid ◽

The Brain

Alzheimer’s disease is a complex and multifactorial condition regulated by both genetics and lifestyle, which ultimately results in the accumulation of β-amyloid (Aβ) and tau proteins in the brain, loss of gray matter, and neuronal death [...]

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18F-labeled 2-phenylbenzoheterocycles with chiral dihydroxyl side chains as β-amyloid imaging probes

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2020.115884 ◽

2021 ◽

Vol 29 ◽

pp. 115884

Author(s):

Yuying Li ◽

Kaixiang Zhou ◽

Wentao Guo ◽

Mengchao Cui

Keyword(s):

Amyloid Imaging ◽

Side Chains ◽

Imaging Probes ◽

Β Amyloid

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Substrate-Specific Activation of α-Secretase by 7-Deoxy-Trans-Dihydronarciclasine Increases Non-Amyloidogenic Processing of β-Amyloid Protein Precursor

Molecules ◽

10.3390/molecules25030646 ◽

2020 ◽

Vol 25 (3) ◽

pp. 646

Author(s):

Yoon Sun Chun ◽

Yoon Young Cho ◽

Oh Hoon Kwon ◽

Dong Zhao ◽

Hyun Ok Yang ◽

...

Keyword(s):

Therapeutic Option ◽

Protein Precursor ◽

App Processing ◽

Plot Analysis ◽

Amyloidogenic Processing ◽

Model Mouse ◽

Amyloid Aβ ◽

Β Amyloid ◽

The Brain ◽

Aβ Production

Accumulation of β-amyloid (Aβ) in the brain has been implicated in the pathology of Alzheimer’s disease (AD). Aβ is produced from the Aβ precursor protein (APP) through the amyloidogenic pathway by β-, and γ-secretase. Alternatively, APP can be cleaved by α-, and γ-secretase, precluding the production of Aβ. Thus, stimulating α-secretase mediated APP processing is considered a therapeutic option not only for decreasing Aβ production but for increasing neuroprotective sAPPα. We have previously reported that 7-deoxy-trans-dihydronarciclasine (E144), the active component of Lycoris chejuensis, decreases Aβ production by attenuating APP level, and retarding APP maturation. It can also improve cognitive function in the AD model mouse. In this study, we further analyzed the activating effect of E144 on α-secretase. Treatment of E144 increased sAPPα, but decreased β-secretase products from HeLa cells stably transfected with APP. E144 directly activated ADAM10 and ADAM17 in a substrate-specific manner both in cell-based and in cell-free assays. The Lineweaver–Burk plot analysis revealed that E144 enhanced the affinities of A Disintegrin and Metalloproteinases (ADAMs) towards the substrate. Consistent with this result, immunoprecipitation analysis showed that interactions of APP with ADAM10 and ADAM17 were increased by E144. Our results indicate that E144 might be a novel agent for AD treatment as a substrate-specific activator of α-secretase.

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Transmissible Endosomal Intoxication: A Balance between Exosomes and Lysosomes at the Basis of Intercellular Amyloid Propagation

Biomedicines ◽

10.3390/biomedicines8080272 ◽

2020 ◽

Vol 8 (8) ◽

pp. 272

Author(s):

Anaïs Bécot ◽

Charlotte Volgers ◽

Guillaume van Niel

Keyword(s):

Amyloid Precursor Protein ◽

Neurodegenerative Diseases ◽

Multivesicular Body ◽

Precursor Protein ◽

Aβ Peptides ◽

Amyloid Aβ ◽

Β Amyloid ◽

Novel Concept ◽

The Brain

In Alzheimer′s disease (AD), endolysosomal dysfunctions are amongst the earliest cellular features to appear. Each organelle of the endolysosomal system, from the multivesicular body (MVB) to the lysosome, contributes to the homeostasis of amyloid precursor protein (APP) cleavage products including β-amyloid (Aβ) peptides. Hence, this review will attempt to disentangle how changes in the endolysosomal system cumulate to the generation of toxic amyloid species and hamper their degradation. We highlight that the formation of MVBs and the generation of amyloid species are closely linked and describe how the molecular machineries acting at MVBs determine the generation and sorting of APP cleavage products towards their degradation or release in association with exosomes. In particular, we will focus on AD-related distortions of the endolysomal system that divert it from its degradative function to favour the release of exosomes and associated amyloid species. We propose here that such an imbalance transposed at the brain scale poses a novel concept of transmissible endosomal intoxication (TEI). This TEI would initiate a self-perpetuating transmission of endosomal dysfunction between cells that would support the propagation of amyloid species in neurodegenerative diseases.

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Pharmacogenetic features of cathepsin B inhibitors that improve memory deficit and reduce β-amyloid related to Alzheimer's disease

Biological Chemistry ◽

10.1515/bc.2010.110 ◽

2010 ◽

Vol 391 (8) ◽

Cited By ~ 25

Author(s):

Vivian Hook ◽

Gregory Hook ◽

Mark Kindy

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Models ◽

Cathepsin B ◽

Memory Deficit ◽

Mutant Site ◽

Amyloid Aβ ◽

Β Amyloid ◽

The Brain ◽

Aβ Production

Abstract Beta-amyloid (Aβ) in the brain is a major factor involved in Alzheimer's disease (AD) that results in severe memory deficit. Our recent studies demonstrate pharmacogenetic differences in the effects of inhibitors of cathepsin B to improve memory and reduce Aβ in different mouse models of AD. The inhibitors improve memory and reduce brain Aβ in mice expressing the wild-type (WT) β-secretase site of human APP, expressed in most AD patients. However, these inhibitors have no effect in mice expressing the rare Swedish (Swe) mutant amyloid precursor protein (APP). Knockout of the cathepsin B decreased brain Aβ in mice expressing WT APP, validating cathepsin B as the target. The specificity of cathepsin B to cleave the WT β-secretase site, but not the Swe mutant site, of APP for Aβ production explains the distinct inhibitor responses in the different AD mouse models. In contrast to cathepsin B, the BACE1 β-secretase prefers to cleave the Swe mutant site. Discussion of BACE1 data in the field indicate that they do not preclude cathepsin B as also being a β-secretase. Cathepsin B and BACE1 could participate jointly as β-secretases. Significantly, the majority of AD patients express WT APP and, therefore, inhibitors of cathepsin B represent candidate drugs for AD.

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