TY - JOUR
T1 - Salivary Lactoferrin Expression in a Mouse Model of Alzheimer’s Disease
AU - Antequera, Desiree
AU - Moneo, Diego
AU - Carrero, Laura
AU - Bartolome, Fernando
AU - Ferrer, Isidro
AU - Proctor, Gordon
AU - Carro, Eva
N1 - Funding Information:
This study was supported by grants from Instituto de Salud Carlos III (FIS18/00118), FEDER, Comunidad de Madrid (S2017/BMD-3700; NEUROMETAB-CM), and CIBERNED (CB07/502).
Funding Information:
We are grateful to the Banner Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona for the provision of human salivary gland samples. The Brain and Body Donation Program has been supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson?s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer?s Disease Core Centre), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer?s Research Centre), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001to the Arizona Parkinson?s Disease Consortium) and the Michael J. Fox Foundation for Parkinson?s Research.
Publisher Copyright:
© Copyright © 2021 Antequera, Moneo, Carrero, Bartolome, Ferrer, Proctor and Carro.
PY - 2021/9/30
Y1 - 2021/9/30
N2 - 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.
AB - 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.
KW - acetylcholine
KW - Alzheimer’s disease
KW - antimicrobial protein
KW - immune system
KW - lactoferrin
KW - muscarinic receptors
KW - saliva
KW - submandibular glands
UR - http://www.scopus.com/inward/record.url?scp=85117132765&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2021.749468
DO - 10.3389/fimmu.2021.749468
M3 - Article
AN - SCOPUS:85117132765
SN - 1664-3224
VL - 12
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 749468
ER -
