Neuroprotective Function of Non-Proteolytic Amyloid-β Chaperones in Alzheimer’s Disease

Sharma, Bhargy; Pervushin, Konstantin

doi:10.5772/intechopen.84238

Cited by 5 publications

(7 citation statements)

References 101 publications

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Section: ■ Resultsmentioning

confidence: 99%

“…In addition to having direct effects of GBP on Aβ, other possibilities could also explain its protective effects. For example, a potential interaction with chaperones could affect folding and assembly of proteins, , and the degradation of misfolded proteins, preventing their toxic effects . Heat shock proteins, for example, were reported to prevent Aβ 40 and Aβ 42 aggregation and unfold misfolded oligomers. − A recent study showed that a mutant form of the Bri2 BRICHOS chaperone was able to block the aggregation of Aβ 42 into toxic species, , suggesting that the potentiation of endogenous chaperones could reduce the neurotoxic effects of the Aβ peptide.…”

Section: Discussionmentioning

confidence: 99%

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Gabapentin Inhibits Multiple Steps in the Amyloid Beta Toxicity Cascade

González-Sanmiguel

Burgos

Bascuñán

et al. 2020

ACS Chem. Neurosci.

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Oligomeric β-amyloid peptide (Aβ) is one of the main neurotoxic agents of Alzheimer's disease (AD). Oligomers associate to neuronal membranes, forming "pore-like" structures that cause intracellular calcium and neurotransmitter dyshomeostasis, leading to synaptic failure and death. Through molecular screening targeting the C terminal region of Aβ, a region involved in the toxic properties of the peptide, we detected an FDA approved compound, gabapentin (GBP), with neuroprotective effects against Aβ toxicity. At micromolar concentrations, GBP antagonized peptide aggregation over time and reduced the Aβ absorbance plateau to 28% of control. In addition, GBP decreased Aβ association to membranes by almost half, and the effects of Aβ on intracellular calcium in hippocampal neurons were antagonized without causing effects on its own. Finally, we found that GBP was able to block the synaptotoxicity induced by Aβ in hippocampal neurons, increasing postsynaptic currents from 1.7 ± 0.9 to 4.2 ± 0.7 fC and mean relative fluorescence intensity values of SV2, a synaptic protein, from 0.7 ± 0.09 to 1.00 ± 0.08. The results show that GBP can interfere with Aβ-induced toxicity by blocking multiple steps, resulting in neuroprotection, which justifies advancing toward additional animal and human studies.

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Section: ■ Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Gabapentin Inhibits Multiple Steps in the Amyloid Beta Toxicity Cascade

González-Sanmiguel

Burgos

Bascuñán

et al. 2020

ACS Chem. Neurosci.

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“…of axonal injury are potential avenues which can be explored for AD theranostics [47]. Our results pave the way for the study of other endogenous proteins with significant potential as a chaperone for aggregation-prone amyloids [48]. This work highlights the importance of the use of modifiable contrast agents with engineered coatings to enhance detection of properties of biocompatible diagnostic probes.…”

Section: Discussionmentioning

confidence: 79%

Conjugates of neuroprotective chaperone L-PGDS provide MRI contrast for detection of amyloid β-rich regions in live Alzheimer’s Disease mouse model brain

Sharma¹,

Grandjean²,

Phillips³

et al. 2020

Preprint

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Endogenous brain proteins can recognize the toxic oligomers of amyloid-β (Aβ) peptides implicated in Alzheimer's disease (AD) and interact with them to prevent their aggregation.Lipocalin-type Prostaglandin D Synthase (L-PGDS) is a major Aβ-chaperone protein in the human cerebrospinal fluid. Here we demonstrate that L-PGDS detects amyloids in diseased mouse brain. Conjugation of L-PGDS with magnetic nanoparticles enhanced the contrast for magnetic resonance imaging. We conjugated the L-PGDS protein with ferritin nanocages to detect amyloids in the AD mouse model brain. We show here that the conjugates administered through intraventricular injections co-localize with amyloids in the mouse brain.These conjugates can target the brain regions through non-invasive intranasal administration, as shown in healthy mice. These conjugates can inhibit the aggregation of amyloids in vitro and show potential neuroprotective function by breaking down the mature amyloid fibrils.

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“…The antibodies and synthetic molecules have an inherent risk of triggering immunogenic reactions in the body. Many non-proteolytic proteins, such as Lipocalin-type Prostaglandin D Synthase (L-PGDS), clusterin, αB-crystallin, and α2-Macroglobulin, act as extracellular chaperones and can inhibit the aggregation of Aβ [34,35]. These endogenous human proteins act as chaperones for misfolded Aβ peptides and show disaggregase activity towards the insoluble Aβ aggregates by breaking them down into monomers.…”

Section: Magnetic Resonance Imaging Probes For Alzheimer's Disease Thmentioning

confidence: 99%

Magnetic Nanoparticles as In Vivo Tracers for Alzheimer’s Disease

Sharma

Pervushin

2020

Magnetochemistry

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Drug formulations and suitable methods for their detection play a very crucial role in the development of therapeutics towards degenerative neurological diseases. For diseases such as Alzheimer's disease, magnetic resonance imaging (MRI) is a non-invasive clinical technique suitable for early diagnosis. In this review, we will discuss the different experimental conditions which can push MRI as the technique of choice and the gold standard for early diagnosis of Alzheimer's disease. Here, we describe and compare various techniques for administration of nanoparticles targeted to the brain and suitable formulations of nanoparticles for use as magnetically active therapeutic probes in drug delivery targeting the brain. We explore different physiological pathways involved in the transport of such nanoparticles for successful entry in the brain. In our lab, we have used different formulations of iron oxide nanoparticles (IONPs) and protein nanocages as contrast agents in anatomical MRI of an Alzheimer's disease (AD) brain. We compare these coatings and their benefits to provide the best contrast in addition to biocompatibility properties to be used as sustainable drug-release systems. In the later sections, the contrast enhancement techniques in MRI studies are discussed. Examples of contrast-enhanced imaging using advanced pulse sequences are discussed with the main focus on important studies in the field of neurological diseases. In addition, T1 contrast agents such as gadolinium chelates are compared with the T2 contrast agents mainly made of superparamagnetic inorganic metal nanoparticles.

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Neuroprotective Function of Non-Proteolytic Amyloid-β Chaperones in Alzheimer’s Disease

Cited by 5 publications

References 101 publications

Gabapentin Inhibits Multiple Steps in the Amyloid Beta Toxicity Cascade

Gabapentin Inhibits Multiple Steps in the Amyloid Beta Toxicity Cascade

Conjugates of neuroprotective chaperone L-PGDS provide MRI contrast for detection of amyloid β-rich regions in live Alzheimer’s Disease mouse model brain

Magnetic Nanoparticles as In Vivo Tracers for Alzheimer’s Disease

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