Searching for an endogenous anti-Alzheimer molecule: identifying small molecules in the brain that slow Alzheimer disease progression by inhibition of β-amyloid aggregation

Meek, Autumn; Simms, Gordon A.; Weaver, Donald F.

doi:10.1503/jpn.120166

Cited by 16 publications

(13 citation statements)

References 29 publications

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“…However, in contrast, 3-HAA in the CSF of NC positively correlated with CSF Aβ42 (r = 0.551, p = 0.0118; Figure 4E), signifying decreased brain Aβ deposition. This agrees with studies showing that 3-HAA dose-dependently inhibits the in-vitro aggregation of Aβ (Meek et al, 2013). As a similar relationship is not seen in AD, this may suggest that other mechanisms leading to Aβ aggregation overwhelm the capacity of 3-HAA to decrease Aβ deposition.…”

Section: Cns and Plasma Concentrations Of Kynurenine Pathway Metabolisupporting

confidence: 90%

Correlation between plasma and CSF concentrations of kynurenine pathway metabolites in Alzheimer's disease and relationship to amyloid-β and tau

Jacobs

Lim

Blennow

et al. 2019

Neurobiology of Aging

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Chronic kynurenine pathway (KP) activation is implicated in Alzheimer's disease (AD) pathophysiology and results in quinolinic acid-induced excitotoxic stimulation of the Nmethyl-D-aspartate receptor. However, most studies focus on plasma and it is unclear if peripheral concentrations reflect brain concentrations and how these may correlate to AD pathophysiology reflected by the AD biomarkers amyloid-β, total-tau (t-tau) or phosphorylated-tau (p-tau). We characterised the KP in matched plasma and cerebrospinal fluid (CSF) samples from 20 AD patients and 18 age-matched control subjects. Plasma concentrations of kynurenine (KYN), 3-hydroxykynurenine (3-HK), anthranilic acid and picolinic acid (PIC) significantly correlated with their respective CSF levels. In AD participants, plasma KYN (r =-0.479, p = 0.033) and PIC (r =-0.650, p = 0.009) inversely correlated with CSF p-tau and t-tau, respectively. Further, in AD CSF, increased 3-HK/KYN ratio correlated with t-tau (r = 0.567, p = 0.009) and p-tau (r = 0.515, p = 0.020). These data support KP involvement in AD pathogenesis and add to the case for the therapeutic modulation of the KP in AD. Highlights (3-5, max 85 characters including spaces per bullet point)  Kynurenine pathway (KP) metabolites correlate in matched plasma and CSF samples  CSF KP metabolites correlate with AD biomarkers, t-tau and p-tau  KP correlation with t-tau and p-tau may suggest mechanistic links

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Section: Cns and Plasma Concentrations Of Kynurenine Pathway Metabolisupporting

confidence: 90%

Correlation between plasma and CSF concentrations of kynurenine pathway metabolites in Alzheimer's disease and relationship to amyloid-β and tau

Jacobs

Lim

Blennow

et al. 2019

Neurobiology of Aging

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“…When in a pro-oxidant environment, 3HAA auto-oxidizes by dimerizing into cinnabarinic acid [39]. 3HAA has been found to prevent β-amyloid aggregation by binding to a specific region within the protein that, in the absence of 3HAA, promotes its misfolding [40]. This represents a potential research area to target for Alzheimer's disease (AD).…”

Section: The 3-hydroxyanthranilic Acid To Anthranilic Acid Ratiomentioning

confidence: 99%

The Role of Tryptophan Metabolites in Musculoskeletal Stem Cell Aging

Anaya

Bollag

Hamrick

et al. 2020

IJMS

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Although aging is considered a normal process, there are cellular and molecular changes that occur with aging that may be detrimental to health. Osteoporosis is one of the most common age-related degenerative diseases, and its progression correlates with aging and decreased capacity for stem cell differentiation and proliferation in both men and women. Tryptophan metabolism through the kynurenine pathway appears to be a key factor in promoting bone-aging phenotypes, promoting bone breakdown and interfering with stem cell function and osteogenesis; however, little data is available on the impact of tryptophan metabolites downstream of kynurenine. Here we review available data on the impact of these tryptophan breakdown products on the body in general and, when available, the existing evidence of their impact on bone. A number of tryptophan metabolites (e.g., 3-hydroxykynurenine (3HKYN), kynurenic acid (KYNA) and anthranilic acid (AA)) have a detrimental effect on bone, decreasing bone mineral density (BMD) and increasing fracture risk. Other metabolites (e.g., 3-hydroxyAA, xanthurenic acid (XA), picolinic acid (PIA), quinolinic acid (QA), and NAD+) promote an increase in bone mineral density and are associated with lower fracture risk. Furthermore, the effects of other tryptophan breakdown products (e.g., serotonin) are complex, with either anabolic or catabolic actions on bone depending on their source. The mechanisms involved in the cellular actions of these tryptophan metabolites on bone are not yet fully known and will require further research as they are potential therapeutic targets. The current review is meant as a brief overview of existing English language literature on tryptophan and its metabolites and their effects on stem cells and musculoskeletal systems. The search terms used for a Medline database search were: kynurenine, mesenchymal stem cells, bone loss, tryptophan metabolism, aging, and oxidative stress.

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“…3-Hydroxy-anthranilic acid and L-phosphoserine, two endogenous brain molecules, bound to the HHQK region of A␤ [13][14][15][16] and were able to inhibit A␤ aggregation [306].…”

Section: Natural Productsmentioning

confidence: 99%

Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes. Disease-Modifying Drugs. Update 2014

Froestl

Pfeifer

Muhs

2014

JAD

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Scientists working in the field of Alzheimer's disease and, in particular, cognitive enhancers, are very productive. The review "Drugs interacting with Targets other than Receptors or Enzymes. Disease-modifying Drugs" was accepted in October 2012. In the last 20 months, new targets for the potential treatment of Alzheimer's disease were identified. Enormous progress was realized in the pharmacological characterization of natural products with cognitive enhancing properties. This review covers the evolution of research in this field through May 2014.

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Searching for an endogenous anti-Alzheimer molecule: identifying small molecules in the brain that slow Alzheimer disease progression by inhibition of β-amyloid aggregation

Cited by 16 publications

References 29 publications

Correlation between plasma and CSF concentrations of kynurenine pathway metabolites in Alzheimer's disease and relationship to amyloid-β and tau

Correlation between plasma and CSF concentrations of kynurenine pathway metabolites in Alzheimer's disease and relationship to amyloid-β and tau

The Role of Tryptophan Metabolites in Musculoskeletal Stem Cell Aging

Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes. Disease-Modifying Drugs. Update 2014

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