A pilot study on the effect of lactoferrin on Alzheimer’s disease pathological sequelae: Impact of the p-Akt/PTEN pathway

Mohamed, Waleed S.; Salama, Rania M.; Schaalan, Mona F.

doi:10.1016/j.biopha.2018.12.118

Cited by 62 publications

(62 citation statements)

References 51 publications

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“…It has been shown that Lf simultaneously enhances antioxidant activity by reducing ROS and enhancing SOD1 and reducing inflammatory markers in AD mice [45] . In a recent study with AD patients, Lf treatment showed significant improvements in antioxidant and anti-inflammatory markers in serum, and reduced Aβ42 and phosphorylated tau levels, as well as improved cognitive function [50] . Lf antioxidant activities have also been described in PD experimental models in which this protein was able to prevent oxidative stress and to upregulate the expression of antioxidant enzymes.…”

Section: Discussionmentioning

confidence: 93%

Decreased salivary lactoferrin levels are specific to Alzheimer's disease

et al. 2020

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Background Evidences of infectious pathogens in Alzheimer's disease (AD) brains may suggest a deteriorated innate immune system in AD pathophysiology. We previously demonstrated reduced salivary lactoferrin (Lf) levels, one of the major antimicrobial proteins, in AD patients. Methods To assess the clinical utility of salivary Lf for AD diagnosis, we examine the relationship between salivary Lf and cerebral amyloid-β (Aβ) load using amyloid-Positron-Emission Tomography (PET) neuroimaging, in two different cross-sectional cohorts including patients with different neurodegenerative disorders. Findings The diagnostic performance of salivary Lf in the cohort 1 had an area under the curve [AUC] of 0•95 (0•911–0•992) for the differentiation of the prodromal AD/AD group positive for amyloid-PET (PET + ) versus healthy group, and 0•97 (0•924–1) versus the frontotemporal dementia (FTD) group. In the cohort 2, salivary Lf had also an excellent diagnostic performance in the health control group versus prodromal AD comparison: AUC 0•93 (0•876–0•989). Salivary Lf detected prodromal AD and AD dementia distinguishing them from FTD with over 87% sensitivity and 91% specificity. Interpretation Salivary Lf seems to have a very good diagnostic performance to detect AD. Our findings support the possible utility of salivary Lf as a new non-invasive and cost-effective AD biomarker. Funding Instituto de Salud Carlos III (FIS15/00780, FIS18/00118), FEDER, Comunidad de Madrid (S2017/BMD-3700; NEUROMETAB-CM), and CIBERNED (PI2016/01) to E.C.; Spanish Ministry of Economy and Competitiveness (SAF2017-85310-R) to J.L.C., and (PSI2017-85311-P) to M.A.; International Centre on ageing CENIE-POCTEP (0348_CIE_6_E) to M.A.; Instituto de Salud Carlos III (PIE16/00021, PI17/01799), to H.B.

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Section: Discussionmentioning

confidence: 93%

Decreased salivary lactoferrin levels are specific to Alzheimer's disease

et al. 2020

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“…However, few clinical trials for AD have explored mitogenic signaling. Those trials included examinations of the following drugs: lactoferrin, which can modulate p‐AKT/PTEN (Mohamed, Salama, & Schaalan, ); neflamapimod, a specific inhibitor of p38MAPK‐alpha (Alam, Blackburn, & Patrick, ); bryostatin 1, an activator of protein kinase C epsilon (Nelson et al, ); tideglusib, an inhibitor of GSK3 (Lovestone et al, ); and lithium, a GSK3 inhibitor (Forlenza et al, ). Although this “targeting mitogenic kinase/signaling” approach has not become mainstream in AD research and drug development, the approach has been established in cancer research and drug development, with success against oncogene‐addicted cancers (e.g., imatinib/Gleevec targeting Bcr‐Abl tyrosine kinase, trastuzumab/Herceptin targeting Neu receptor).…”

Section: Effects Of Cell Cycle Interfering Drugs On Ad Modelsmentioning

confidence: 99%

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

et al. 2020

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The cell cycle and its regulators are validated targets for cancer drugs. Reagents that target cells in a specific cell cycle phase (e.g., antimitotics or DNA synthesis inhibitors/replication stress inducers) have demonstrated success as broad‐spectrum anticancer drugs. Cyclin‐dependent kinases (CDKs) are drivers of cell cycle transitions. A CDK inhibitor, flavopiridol/alvocidib, is an FDA‐approved drug for acute myeloid leukemia. Alzheimer's disease (AD) is another serious issue in contemporary medicine. The cause of AD remains elusive, although a critical role of latent amyloid‐beta accumulation has emerged. Existing AD drug research and development targets include amyloid, amyloid metabolism/catabolism, tau, inflammation, cholesterol, the cholinergic system, and other neurotransmitters. However, none have been validated as therapeutically effective targets. Recent reports from AD‐omics and preclinical animal models provided data supporting the long‐standing notion that cell cycle progression and/or mitosis may be a valid target for AD prevention and/or therapy. This review will summarize the recent developments in AD research: (a) Mitotic re‐entry, leading to the “amyloid‐beta accumulation cycle,” may be a prerequisite for amyloid‐beta accumulation and AD pathology development; (b) AD‐associated pathogens can cause cell cycle errors; (c) thirteen among 37 human AD genetic risk genes may be functionally involved in the cell cycle and/or mitosis; and (d) preclinical AD mouse models treated with CDK inhibitor showed improvements in cognitive/behavioral symptoms. If the “amyloid‐beta accumulation cycle is an AD drug target” concept is proven, repurposing of cancer drugs may emerge as a new, fast‐track approach for AD management in the clinic setting.

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“…Owing to its iron-binding activity, lactoferrin is a multifunctional protein that exhibits antibacterial, antiviral, antifungal, antioxidant, immunomodulatory, anti-cancer, anti-inflammatory and anti-allergenic properties [ 160 , 162 , 163 , 164 ]. Moreover, while there is evidence of lactoferrin presence within the human brain, its levels are substantially increased in AD patients and those with related neurodegenerative disorders, which could be attributed to its Aβ-binding ability [ 165 , 166 , 167 ]. Therefore, lactoferrin has been associated with AD pathogenesis, as it has been detected in the amyloid plaques, NFTs and microglia of AD brains [ 164 , 165 ].…”

Section: Saliva Biomarkersmentioning

confidence: 99%

“…Moreover, while there is evidence of lactoferrin presence within the human brain, its levels are substantially increased in AD patients and those with related neurodegenerative disorders, which could be attributed to its Aβ-binding ability [ 165 , 166 , 167 ]. Therefore, lactoferrin has been associated with AD pathogenesis, as it has been detected in the amyloid plaques, NFTs and microglia of AD brains [ 164 , 165 ]. Studies on AD patients are still limited, but there is strong evidence that the salivary levels of lactoferrin significantly decrease when compared to healthy controls and elderly subjects [ 139 , 148 , 164 , 168 ].…”

Section: Saliva Biomarkersmentioning

confidence: 99%

Body Fluid Biomarkers for Alzheimer’s Disease—An Up-To-Date Overview

2020

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Neurodegeneration is a highly complex process which is associated with a variety of molecular mechanisms related to ageing. Among neurodegenerative disorders, Alzheimer’s disease (AD) is the most common, affecting more than 45 million individuals. The underlying mechanisms involve amyloid plaques and neurofibrillary tangles (NFTs) deposition, which will subsequently lead to oxidative stress, chronic neuroinflammation, neuron dysfunction, and neurodegeneration. The current diagnosis methods are still limited in regard to the possibility of the accurate and early detection of the diseases. Therefore, research has shifted towards the identification of novel biomarkers and matrices as biomarker sources, beyond amyloid-β and tau protein levels within the cerebrospinal fluid (CSF), that could improve AD diagnosis. In this context, the aim of this paper is to provide an overview of both conventional and novel biomarkers for AD found within body fluids, including CSF, blood, saliva, urine, tears, and olfactory fluids.

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A pilot study on the effect of lactoferrin on Alzheimer’s disease pathological sequelae: Impact of the p-Akt/PTEN pathway

Cited by 62 publications

References 51 publications

Decreased salivary lactoferrin levels are specific to Alzheimer's disease

Decreased salivary lactoferrin levels are specific to Alzheimer's disease

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

Body Fluid Biomarkers for Alzheimer’s Disease—An Up-To-Date Overview

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