Comparison of molecular functions of lactoferrin and amyloid precursor protein support their functional roles in the innate immune system and links with infection in Alzheimer’s disease risk.

Systemic and brain-localised inflammations are hallmark features of ageing that are further elevated in dementia and particularly in Alzheimer’s disease (AD). However, although present in other chronic diseases co-associated with AD, the potential role of chronic inflammation as a causative risk factor for cognitive decline and AD may have been overlooked.  Peptide-derived forms of amyloid precursor protein (APP) present as amyloid beta peptides (Aβ) together with intact and peptide-derived forms of lactoferrin (Lf), are both present and co-localised in amyloid deposits in the eye and in senile plaques in the brain.  It is proposed that their co-incidence supports the hypothesis that APP and Lf exert similar and mutually supportive biological roles.  There is a strong evidence base for the protective role of Lf in host defence during infection with its very high affinity to ferric iron representing a front line of attack against pathogenic microbes and binding interactions that scavenge virus particles.  Lf turn-over involves release of peptides exerting anti-inflammatory effects via multiple pathways, representing a ‘self-regulating’ biological system.  We present compelling evidence that APP exerts a similar functional role to Lf as a signaling molecule of the innate immune system, that can account for its co-expression with Lf in AD.  The hypothesis is supported by membrane-localisation of APP, metal and other ligand binding capacities, involvement in chemo-attraction of immune cells to the endothelium and cell binding to the extracellular matrix.  Consistent evidence supports that systemic APP expression is correlated with inflammation status in conditions of chronic disease and ageing, and is lowered by treatments that regulate inflammation.  While APP over-expression occurs in pro-inflammatory conditions other than infection, it is possible that the co-incidence of APP and Lf is specific for the presence of infection-mediated causes of APP upregulation.  If APP does participate in the innate immune response, then the relationship between development of chronic inflammation and onset of APP over-expression represents a new basis for understanding AD risk.  Furthermore, if substantiated, managing longitudinal changes in APP expression and amyloid-mediated AD pathology, by treating infection and chronic inflammation, offer promising targets for AD prevention and potentially therapy.