Amyloid-β and Tau Dynamics in Human Brain Interstitial Fluid in Patients with Suspected Normal Pressure Hydrocephalus

Herukka, Sanna‐Kaisa; Rummukainen, Jaana; Ihalainen, Jouni; Fraunberg, Mikael von und zu; Koivisto, Anne M.; Nerg, Ossi; Puli, Lakshman; Seppälä, Toni T.; Zetterberg, Henrik; Pyykkö, Okko T.; Helisalmi, Seppo; Tanila, Heikki; Alafuzoff, Irina; Hiltunen, Mikko; Rinne, Jaakko; Soininen, Hilkka; Jääskeläinen, Juha E.; Leinonen, Ville

doi:10.3233/jad-142862

Cited by 40 publications

(43 citation statements)

References 26 publications

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“…We circulated 200 mg/mL HDL in our experiments, similar to what has previously been published for other in vitro studies (Datta et al, 2001;Robert et al, 2013a). Although previous in vitro studies have also used similar Ab levels (Takamatsu et al, 2014;Xu et al, 2013), the Ab dose used in this study corresponds to a supra physiological concentration of Ab compared to human brain, CSF or cerebral interstitial fluid, a limitation imposed by the detection limits of our assay (Brody et al, 2008;Seubert et al, 1992;Herukka et al, 2015) As well, although we could demonstrate that our bioengineered vessels are able to produce NO under physiologically relevant stimuli, our current scaffolding materials are too stiff to permit measurement of vascular compliance. Engineering improvements that explore alternative materials and enable scalable production of bioengineered vessels are also important avenues for future studies.…”

Section: Discussionsupporting

confidence: 51%

[O2–04–01]: Clearance of Beta‐amyloid Is Facilitated by Apolipoprotein E and Circulating High‐density Lipoproteins in Bioengineered Human Vessels

Robert

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Soo

et al. 2017

Alzheimer's & Dementia

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Amyloid plaques, consisting of deposited beta-amyloid (Ab), are a neuropathological hallmark of Alzheimer's Disease (AD). Cerebral vessels play a major role in AD, as Ab is cleared from the brain by pathways involving the cerebrovasculature, most AD patients have cerebrovascular amyloid (cerebral amyloid angiopathy (CAA), and cardiovascular risk factors increase dementia risk. Here we present a notable advance in vascular tissue engineering by generating the first functional 3-dimensioinal model of CAA in bioengineered human vessels. We show that lipoproteins including brain (apoE) and circulating (high-density lipoprotein, HDL) synergize to facilitate Ab transport across bioengineered human cerebral vessels. These lipoproteins facilitate Ab42 transport more efficiently than Ab40, consistent with Ab40 being the primary species that accumulates in CAA. Moreover, apoE4 is less effective than apoE2 in promoting Ab transport, also consistent with the well-established role of apoE4 in Ab deposition in AD.

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Section: Discussionsupporting

confidence: 51%

[O2–04–01]: Clearance of Beta‐amyloid Is Facilitated by Apolipoprotein E and Circulating High‐density Lipoproteins in Bioengineered Human Vessels

Robert

Button

Soo

et al. 2017

Alzheimer's & Dementia

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“…; Herukka et al . ). To investigate the impact of starting monomer concentration, AβOs were formed at various concentrations (100‐0.03 μM) and analyzed via size exclusion chromatography (SEC) with dot immunoblotting detection.…”

Section: Resultsmentioning

confidence: 97%

A novel crosslinking protocol stabilizes amyloid β oligomers capable of inducing Alzheimer's‐associated pathologies

Cline

Das

Bicca

et al. 2019

Journal of Neurochemistry

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Amyloid β oligomers (AβOs) accumulate early in Alzheimer's disease (AD) and experimentally cause memory dysfunction and the major pathologies associated with AD, for example, tau abnormalities, synapse loss, oxidative damage, and cognitive dysfunction. In order to develop the most effective AβO‐targeting diagnostics and therapeutics, the AβO structures contributing to AD‐associated toxicity must be elucidated. Here, we investigate the structural properties and pathogenic relevance of AβOs stabilized by the bifunctional crosslinker 1,5‐difluoro‐2,4‐dinitrobenzene (DFDNB). We find that DFDNB stabilizes synthetic Aβ in a soluble oligomeric conformation. With DFDNB, solutions of Aβ that would otherwise convert to large aggregates instead yield solutions of stable AβOs, predominantly in the 50–300 kDa range, that are maintained for at least 12 days at 37°C. Structures were determined by biochemical and native top–down mass spectrometry analyses. Assayed in neuronal cultures and i.c.v.‐injected mice, the DFDNB‐stabilized AβOs were found to induce tau hyperphosphorylation, inhibit choline acetyltransferase, and provoke neuroinflammation. Most interestingly, DFDNB crosslinking was found to stabilize an AβO conformation particularly potent in inducing memory dysfunction in mice. Taken together, these data support the utility of DFDNB crosslinking as a tool for stabilizing pathogenic AβOs in structure‐function studies.

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“…In this study, the basal mean CSF concentration of Aβ42 was 179 ± 101 pg/ml (i.e., 0.04 nM, n = 46; Table 5); this concentration aligns with the reported CSF Aβ42 levels that ranged from 144 to 500 pg/ml [4, 34–36] corresponding to 0.035–0.1 nM, in patients with AD ( n = 100) [34] or prodromal/early-stage AD ( n = 100) [35, 36], as measured by ELISA or MS. Furthermore, brain Aβ42 measures vary in the AD literature, but the reported microdialysis studies in humans have shown that brain interstitial soluble Aβ42 are approximately equivalent to CSF Aβ42 levels [37, 38], and, therefore, the latter can be used as a suitable surrogate for brain pharmacokinetic–pharmacodynamic analyses. Thus, when comparing the ratio of brain tramiprosate : Aβ42, there is an approximately 1300- to 3700-fold excess of tramiprosate over soluble Aβ42 at the steady state based on tramiprosate measured in the brain from patients with AD (Table 4), sufficient to exert a full therapeutic effect of tramiprosate.…”

Section: Resultsmentioning

confidence: 99%

Elucidating the Aβ42 Anti-Aggregation Mechanism of Action of Tramiprosate in Alzheimer’s Disease: Integrating Molecular Analytical Methods, Pharmacokinetic and Clinical Data

et al. 2017

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BackgroundAmyloid beta (Aβ) oligomers play a critical role in the pathogenesis of Alzheimer’s disease (AD) and represent a promising target for drug development. Tramiprosate is a small-molecule Aβ anti-aggregation agent that was evaluated in phase III clinical trials for AD but did not meet the primary efficacy endpoints; however, a pre-specified subgroup analysis revealed robust, sustained, and clinically meaningful cognitive and functional effects in patients with AD homozygous for the ε4 allele of apolipoprotein E4 (APOE4/4 homozygotes), who carry an increased risk for the disease. Therefore, to build on this important efficacy attribute and to further improve its pharmaceutical properties, we have developed a prodrug of tramiprosate ALZ-801 that is in advanced stages of clinical development. To elucidate how tramiprosate works, we investigated its molecular mechanism of action (MOA) and the translation to observed clinical outcomes.ObjectiveThe two main objectives of this research were to (1) elucidate and characterize the MOA of tramiprosate via an integrated application of three independent molecular methodologies and (2) present an integrated translational analysis that links the MOA, conformation of the target, stoichiometry, and pharmacokinetic dose exposure to the observed clinical outcome in APOE4/4 homozygote subjects.MethodWe used three molecular analytical methods—ion mobility spectrometry–mass spectrometry (IMS–MS), nuclear magnetic resonance (NMR), and molecular dynamics—to characterize the concentration-related interactions of tramiprosate versus Aβ42 monomers and the resultant conformational alterations affecting aggregation into oligomers. The molecular stoichiometry of the tramiprosate versus Aβ42 interaction was further analyzed in the context of clinical pharmacokinetic dose exposure and central nervous system Aβ42 levels (i.e., pharmacokinetic–pharmacodynamic translation in humans).ResultsWe observed a multi-ligand interaction of tramiprosate with monomeric Aβ42, which differs from the traditional 1:1 binding. This resulted in the stabilization of Aβ42 monomers and inhibition of oligomer formation and elongation, as demonstrated by IMS–MS and molecular dynamics. Using NMR spectroscopy and molecular dynamics, we also showed that tramiprosate bound to Lys16, Lys28, and Asp23, the key amino acid side chains of Aβ42 that are responsible for both conformational seed formation and neuronal toxicity. The projected molar excess of tramiprosate versus Aβ42 in humans using the dose effective in patients with AD aligned with the molecular stoichiometry of the interaction, providing a clear clinical translation of the MOA. A consistent alignment of these preclinical-to-clinical elements describes a unique example of translational medicine and supports the efficacy seen in symptomatic patients with AD. This unique “enveloping mechanism” of tramiprosate also provides a potential basis for tramiprosate dose selection for patients with homozygous AD at earlier stages of disease.ConclusionWe have identifie...

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Amyloid-β and Tau Dynamics in Human Brain Interstitial Fluid in Patients with Suspected Normal Pressure Hydrocephalus

Cited by 40 publications

References 26 publications

[O2–04–01]: Clearance of Beta‐amyloid Is Facilitated by Apolipoprotein E and Circulating High‐density Lipoproteins in Bioengineered Human Vessels

[O2–04–01]: Clearance of Beta‐amyloid Is Facilitated by Apolipoprotein E and Circulating High‐density Lipoproteins in Bioengineered Human Vessels

A novel crosslinking protocol stabilizes amyloid β oligomers capable of inducing Alzheimer's‐associated pathologies

Elucidating the Aβ42 Anti-Aggregation Mechanism of Action of Tramiprosate in Alzheimer’s Disease: Integrating Molecular Analytical Methods, Pharmacokinetic and Clinical Data

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