Salivary Lactoferrin Expression in a Mouse Model of Alzheimer's Disease.

Desiree Antequera,Eva Carro,Laura Carrero,Isidro Ferrer,Fernando Bartolome,Gordon Proctor,Diego Moneo

doi:10.3389/fimmu.2021.749468

Abstract

In the last few years, microbial infection and innate immune theories have been proposed as an alternative approach explaining the etiopathogenesis and origin of Alzheimer’s disease (AD). Lactoferrin, one of the main antimicrobial proteins in saliva, is an important modulator of immune response and inflammation, and represents an important defensive element by inducing a broad spectrum of antimicrobial effects against microbial infections. We demonstrated that lactoferrin levels in saliva are decreased in prodromal and dementia stages of AD compared with healthy subjects. That finding seems to be specific to cerebral amyloid-β (Aβ) load as such observation was not observed in healthy elderly controls or those subjects with frontotemporal dementia. In the present study, we analysed salivary lactoferrin levels in a mouse model of AD. We observed robust and early reduction of lactoferrin levels in saliva from 6- and 12-month-old APP/PS1 mice. Because saliva is secreted by salivary glands, we presume that deregulation in salivary glands resulting in reduced salivary lactoferrin levels may occur in AD. To test this hypothesis, we collected submandibular glands from APP/PS1 mice, as well as submandibular gland tissue from AD patients and we analysed the expression levels of key components of the salivary protein signalling pathway. A significant reduction in M3 receptor levels was found along with decreased acetylcholine (Ach) levels in submandibular glands from APP/PS1 mice. Similarly, a reduction in M3 receptor levels was observed in human submandibular glands from AD patients but in that case, the Ach levels were found increased. Our data suggest that the ACh-mediated M3 signalling pathway is impaired in salivary glands in AD, resulting in salivary gland dysfunction and reduced salivary lactoferrin secretion.

Highlights

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with key pathological hallmarks including amyloid plaques, neurofibrillary tangles, and neurodegeneration [1, 2]
More recently we have shown that reduced salivary lactoferrin levels correlate with increased cerebral amyloid-b (Ab) and this observation is specific to mild cognitive impairment (MCI) and AD patients but not to healthy elderly controls or patients with frontotemporal dementia [27]
We found that salivary lactoferrin levels were significantly lower in 6(p < 0.05; Figure 1A) and 12- (p < 0.05; Figure 1B) monthold transgenic APP/PS1 mice compared with age-matched WT mice

Summary

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with key pathological hallmarks including amyloid plaques, neurofibrillary tangles, and neurodegeneration [1, 2]. A number of studies show strong evidence proving the presence of microbial infectious in AD brains, including viruses, bacteria and fungi [4,5,6,7,8,9,10,11]. Lactoferrin represents an important defensive element by inducing a broad spectrum of antimicrobial effects against bacteria, fungi, protozoa, viruses and yeasts [18]. It plays an important role in regulating the oral microbiota and the inflammatory state of the oral mucosa [19] and contributes to maintaining the symbiosis in the host-microbiome relationship in AD [20]. Other physiological functions of lactoferrin include antioxidant activities, neuroprotection, immune response regulation, anti-inflammatory and anticarcinogenic potential [21,22,23,24,25]

Methods

Results

Conclusion