There is an increasing focus in the research community on the role of chronic inflammation in the development of Alzheimer's disease. With age, the background level of inflammatory signaling rises as the immune system constantly responds to signs of damage and dysfunction. Immune cells become overactive. In the case of the innate immune cells known as monocytes, that give rise to macrophages, an inflammatory background shifts their focus away from supporting processes of regeneration and tissue maintenance, and into a more aggressive and inflammatory state. This has detrimental effects on long-term health, and contributes to the onset of many different age-related conditions.
Alzheimer's disease (AD) is the most common neurodegenerative disease ultimately manifesting as clinical dementia. Despite considerable effort and ample experimental data, the role of neuroinflammation related to systemic inflammation is still unsettled. While the implication of microglia is well recognized, the exact contribution of peripheral monocytes and macrophages is still largely unknown, especially concerning their role in the various stages of AD.
AD develops over decades and its clinical manifestation is preceded by subjective memory complaints (SMC) and mild cognitive impairment (MCI); thus, the question arises how the peripheral innate immune response changes with the progression of the disease. To further investigate the roles of monocytes and macrophages in the progression of AD we assessed their phenotypes and functions in patients at SMC, MCI, and AD stages and compared them with cognitively healthy controls. We also conceptualised an idealised mathematical model to explain the functionality of monocytes/macrophages along the progression of the disease.
We show that there are distinct phenotypic and functional changes in monocyte and macrophage populations as the disease progresses. Higher free radical production upon stimulation could already be observed for the monocytes of SMC patients. The most striking results show that activation of peripheral monocytes (hyperactivation) is the strongest in the MCI group, at the prodromal stage of the disease. Monocytes exhibit significantly increased chemotaxis, free radical production, and cytokine production in response to TLR2 and TLR4 stimulation. Thus our data suggest that the peripheral innate immune system is activated during the progression from SMC through MCI to AD, with the highest levels of activation being in MCI subjects and the lowest in AD patients.