Dietary Lactoferrin Supplementation Prevents Memory Impairment and Reduces Amyloid-β Generation in J20 Mice

Abdelhamid, Mona; Jung, Cha-Gyun; Zhou, Chunyu; Abdullah, Mohammad; Nakano, Manabu; Wakabayashi, Hiroyuki; Abe, Fumiaki; Michikawa, Makoto

doi:10.3233/jad-191181

Cited by 27 publications

(35 citation statements)

References 65 publications

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“…To our surprise, we observed no protective effects of 16 weeks' Lf intervention on cognitive function from both the young and middle-aged APP/PS1 mice; we further demonstrated that almost no key markers involved in Aβ metabolism (IDE, ADAM10, BACE1, and cathepsin B), tau phosphorylation (p-tau ser396&404), neuro-inflammation (GFAP and Ibα1), and synaptic plasticity (BDNF and PSD95) were altered post Lf intervention for both young and middle-aged APP/PS1 mice. This is also contradictory to the studies by Abdelhamid et al (31) and Guo et al (8). We postulate that the following reasons might explain the absence of beneficial effects of Lf on cognition.…”

Section: Discussioncontrasting

confidence: 85%

“…For example, Carro et al (30) reported that healthy individuals with low salivary lactoferrin levels had a higher likelihood (more than 77%) of developing AD. Lf administration (orally or intranasally) could improve cognitive function in both AD patients (7), APP/PS1 mice (8) and AβPP (J20) mice (31). Our study was the very first to explore whether Lf intervention on cognition might be age-dependent by using both the young and middle-aged APP/PS1 mice.…”

Section: Discussionmentioning

confidence: 95%

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Dietary lactoferrin has differential effects on gut microbiota in young versus middle-aged APPswe/PS1dE9 transgenic mice but no effects on cognitive function

Zhou

Wang

Luo

et al. 2021

Food & Nutrition Research

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Background: Existing evidence suggest that lactoferrin might be beneficial for Alzheimer’s disease, while precise mechanisms are not fully elucidated. Objective: To determine the effects of lactoferrin intervention on cognitive function from APPswe/PS1dE9 (APP/PS1) mice, and potential mechanisms involved. Design: Both the young and middle-aged male APP/PS1 mice were divided into the control and lactoferrin intervention groups with 16 weeks’ intervention. Results: Lactoferrin had no effects on cognitive function for both the young and middle-aged mice, and no key markers involved in Aβ, tau pathology, neuro-inflammation and synaptic plasticity were altered after lactoferrin intervention. With regards to gut microbiota profiles, in the young APP/PS1 mice, lactoferrin elevated the α diversity index including ACE and Chao 1, and reduced the relative abundance of the genera Bacteroides and Alistipes and elevated Oscillibacter; in addition, Oscillibacter, Anaerotruncus, EF096579_g, EU454405_g, Mollicutes_RF39, EU474361_g, EU774448_g, and EF096976_g were specifically abundant via linear discriminant analysis with effect size (LEfSe) analysis. In the middle-aged APP/PS1 mice, the relative abundance of the phylum Proteobacteria, as well as the genera Oscillospira, Coprococcus, and Ruminococcus was significantly reduced post lactoferrin; additionally, S24_7, Bacteroidia, Bacteroidetes, and Methylobacterium were specific via LEfSe analysis in the lactoferrin group. Conclusions: Dietary lactoferrin might be beneficial for gut microbiota homeostasis although it might have no effects on cognition.

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Section: Discussioncontrasting

confidence: 85%

Section: Discussionmentioning

confidence: 95%

Dietary lactoferrin has differential effects on gut microbiota in young versus middle-aged APPswe/PS1dE9 transgenic mice but no effects on cognitive function

Zhou

Wang

Luo

et al. 2021

Food & Nutrition Research

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“…A similar mechanism in which amyloidogenic processing of APP is modulated by neuroinflammation requires interferon-induced transmembrane 3 to potentiate γ-secretase activity [ 60 ]. Lf elevation in response to a microbial insult may offer a mechanistic connection between an innate immune response and Aβ production as well as explain some of the acute protective mechanisms reported for Lf in AD [ 61 , 62 ]. However, sustained production of Aβ under chronic Lf produced by the AD-related microgliosis (also potentially receiving contributions from astrocytosis or peripheral plasma) [ 31 ] may lead to Aβ deposition.…”

Section: Discussionmentioning

confidence: 99%

The acute phase protein lactoferrin is a key feature of Alzheimer’s disease and predictor of Aβ burden through induction of APP amyloidogenic processing

et al. 2021

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Amyloidogenic processing of the amyloid precursor protein (APP) forms the amyloid-β peptide (Aβ) component of pathognomonic extracellular plaques of AD. Additional early cortical changes in AD include neuroinflammation and elevated iron levels. Activation of the innate immune system in the brain is a neuroprotective response to infection; however, persistent neuroinflammation is linked to AD neuropathology by uncertain mechanisms. Non-parametric machine learning analysis on transcriptomic data from a large neuropathologically characterised patient cohort revealed the acute phase protein lactoferrin (Lf) as the key predictor of amyloid pathology. In vitro studies showed that an interaction between APP and the iron-bound form of Lf secreted from activated microglia diverted neuronal APP endocytosis from the canonical clathrin-dependent pathway to one requiring ADP ribosylation factor 6 trafficking. By rerouting APP recycling to the Rab11-positive compartment for amyloidogenic processing, Lf dramatically increased neuronal Aβ production. Lf emerges as a novel pharmacological target for AD that not only modulates APP processing but provides a link between Aβ production, neuroinflammation and iron dysregulation.

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“…Both the intensity and number of LF-positive depositions increased with age. The up-regulation of LF in the brains of both AD patients and transgenic mice with AD indicated an important protective role for LF in infected AD-brain tissue [53]. It is tempting to speculate that the high consumption of LF in AD could lead to reduced LF levels over time, particularly when AD is promoted by long-term chronic infection.…”

Section: Low Salivary Lactoferrin Could Promote Transfer Of Oral Bacteria and Tissue Inflammatory Mediators To The Brainmentioning

confidence: 99%

Low levels of salivary lactoferrin may affect oral dysbiosis and contribute to Alzheimer’s disease: A hypothesis

Olsen

Singhrao

2021

Medical Hypotheses

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Dietary Lactoferrin Supplementation Prevents Memory Impairment and Reduces Amyloid-β Generation in J20 Mice

Cited by 27 publications

References 65 publications

Dietary lactoferrin has differential effects on gut microbiota in young versus middle-aged APPswe/PS1dE9 transgenic mice but no effects on cognitive function

Dietary lactoferrin has differential effects on gut microbiota in young versus middle-aged APPswe/PS1dE9 transgenic mice but no effects on cognitive function

The acute phase protein lactoferrin is a key feature of Alzheimer’s disease and predictor of Aβ burden through induction of APP amyloidogenic processing

Low levels of salivary lactoferrin may affect oral dysbiosis and contribute to Alzheimer’s disease: A hypothesis

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