Background

Alzheimer’s disease (AD) is the most common neurodegenerative disease and is characterized by cognitive impairment, amyloid-β (Aβ) deposition, and neurofibrillary tangle formation [1,2,3,4,5]. Increasing evidence suggests that immune mechanisms contribute to the pathogenesis of AD including reactive microgliosis in postmortem samples, increased microglial activation marker, translocator protein (TSPO), binding on positron emission tomography (PET), [6] and increased pro-inflammatory cytokines such as interleukin (IL)-6, IL-1β, TNF, and IFN-γ in the cerebrospinal fluid and serum [7,8,9,10,11]. Thus, neuroinflammation is potentially a target for immunomodulatory therapies [12, 13].

Genome-wide association studies implicate immune system dysfunction, particularly in myeloid-derived cells, as immune-related genes coding for triggering receptor expressed on myeloid cells 2 (TREM2) and CD33 confer increased risk for AD susceptibility [14,15,16,17,18]. Current studies focus on microglia, resident myeloid cells of the brain, throughout AD pathogenesis, but recent literature in neurodegenerative diseases suggest extensive neuro-immune cross-talk between the brain and peripheral immune system [19,20,21,22]. This cross-talk may derive either directly or indirectly from peripheral immune cells in the presence of a compromised blood brain barrier (BBB) such as in neurodegenerative disease [23,24,25]. Additionally during inflammatory insult and microglial depletion, peripheral macrophage engraftment into the CNS was observed with these cells retaining a distinct and lasting transcriptional and functional identity [26]. Thus peripheral immune myeloid cells could modulate disease progression and outcomes in the CNS. The accessibility of these peripheral myeloid cells, and the lack of accessibility to CNS microglia, prompted a detailed examination of blood monocyte populations during the pathoprogression of AD.

Immature and mature monocytes, here-after denoted as “peripheral myeloid cells,” originate from hematopoietic stem cells and mature into peripheral monocytes with the capability of differentiating into macrophages once they enter tissue parenchyma [27,28,29,30,31]. Changes and shifts in peripheral myeloid populations are indicators of disease onset and progression for a multitude of diseases; the pro-inflammatory phenotypes have direct effects on their specific disease [32,33,34,35,36,37,38,39,40]. A detailed analysis of peripheral monocyte population and phenotype changes have not been documented thoroughly in AD progression.

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that exhibit robust suppressive function on T cell proliferation and mature myeloid cell function which has made them a target of multiple immunomodulatory therapies [41,42,26]. Additionally, complex networks and signaling cascades involving additional cells outside our examination might assist in dictating inflammatory environments and cell phenotypes. Examination of these cells, both individually and in concert with each other, will help establish a more definitive immune environment during AD and through its course.

Conclusions

This study documents that peripheral monocytes are pro-inflammatory in advancing stages of AD but not in prodromal AD. The pro-inflammatory responses of monocytes from prodromal AD patients are suppressed while advancing AD patients monocytes lose this suppression, and become activated and pro-inflammatory. Numbers and suppressive functions of MDSCs are increased in prodromal AD and decreased in patients with advancing AD and correlate with pro-inflammatory expression of AD monocytes. MDSCs also suppress Tresp which can readily enter the CNS, and loss of T effector suppression can significantly enhance inflammatory disease pathology. These findings provide a novel inflammatory paradigm that may have confounded early therapeutic interventions and provides a new basis for how future studies and treatments should be designed. Additionally, we have documented the significant impact of AD MDSCs on immune cell subsets. Understanding the role of early enhanced immunosuppression in prodromal AD and the subsequent dysfunction of this process in AD dementia may lead to novel therapeutic strategies.