Alzheimer’s disease (AD), the most common neurodegenerative disorder with progressive memory and cognitive loss, is affecting almost 50 million people worldwide, and the incidence of AD is increasing rapidly with the ageing of the world population [1]. The medical care and nursing cost of AD is enormous [2–4].
The main neuropathological features of AD are neuroinflammation, neurofibrillary tangles (NFTs) formed by intracellular accumulation of hyperphosphorylated Tau (p-Tau) protein, neuritic plaques formed from amyloid-β1−42/1−40 (Aβ1−42/1−40), synapse and neuronal loss, and astroglial proliferation. Major pathogenic hypotheses for AD focus on the Aβ cascade and p-Tau accumulation. However, clinical trials using designed to test the effects of inhibiting Aβ1−42 production by β-secretase inhibitor, clearing Aβ1−42 by monoclonal antibodies, and inhibiting p-Tau by leuco-methylthioninium bis (hydromethanesulfonate; LMTM), have all failed to demonstrate clinical efficacy [1, 5–7]. Thus, the hypotheses of Aβ cascade and p-Tau have been challenged [5–11].
Accumulating studies suggests that neuroinflammation plays an early and crucial role in the genesis of AD pathology [12]. Microglia, the main resident immune cells in the central nervous system (CNS) act as vigilant housekeepers in the adult brain; they activate immediately if the blood-brain barrier (BBB) is disrupted, and they switch their behavior from patrolling to shielding the injured site [13]. Misfolded and aggregated Aβ1−42 and p-Tau, which can bind to pattern recognition receptors (PRRs) on microglia and astrocytes, trigger innate immune response to release inflammatory mediators, which in turn contribute to disease progression and severity [12, 14–18]. Genome-wide analysis suggests that several genes, encoding for glial clearance of Aβ1−42 and the inflammatory reaction, increase the risk of sporadic AD [19–20]. In the pathogenesis of AD, microglia might have a double-edged sword role. At the early stage of AD, microglia protect the brain from the toxic effects of Aβ1−42 by phagocytizing and clearing Aβ [21]. While, as AD progresses, microglia lose their Aβ-clearing capabilities, the expression of microglial Aβ receptors and Aβ-degrading enzymes with persistent production of pro-inflammatory cytokines, results in Aβ deposition. Moreover, complement and microglia mediate the early loss of synapses AD mouse models [22].
While the brain traditionally has been regarded as an immune-privileged organ protected by the BBB, there are interactions between the brain and peripheral organs that have a significant role in the development and progression of AD [23]. Neuroinflammation is closely related to peripheral immunity, especially in the late stage of AD, because the BBB is impaired and, hence, peripheral immune cells and inflammatory molecules enter the brain parenchyma [24, 25]. There is evidence that circulating neutrophils can extravasate and surround Aβ deposits, where they secrete interleukin-17 (IL-17) and neutrophil extracellular traps (NETs). Moreover, inhibiting neutrophil trafficking or depleting these cells reduces AD-like neuropathological changes and improves memory in AD Tg mice [26].
In recent years, the role of peripheral innate immunity in the pathogenesis of AD has gained more attention [27, 28]. Several studies have found that circulating bone marrow-derived macrophages (BMDMs) can enter brain tissue, where they serve as bone marrow-derived microglia that more efficiently phagocytize Aβ1−40/1−42 compared to resident microglial cells [29, 30]. Selective ablation of bone marrow-derived dendritic cells increases amyloid plaques in AD mouse models [31]. Increased cerebral infiltration of monocytes, either by elevating the level of circulating monocytes or by weekly treatment with glatiramer acetate (which simulates myelin basic protein), substantially attenuated disease progression in an AD mouse model [32]. Indeed, prior to these observations, monocytic cells derived from bone marrow stem cells had been used to treat AD [33], while long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) prior to the onset of AD offered protection against AD [34–36]. In November of 2019, sodium oligomannate (GV-971), a marine algae-derived oral oligosaccharide, was approved for AD treatment by the Chinese Food and Drug Administration based on its ability to alleviate neuroinflammation by regulating gut microbiota and inhibiting the brain infiltration of peripheral T helper (Th) 1 cells [37].
In dominantly inherited AD and Down syndrome, plasma Aβ42 levels increased significantly 15 years before the onset of symptoms compared with normal people [38, 39]. Moreover, in the parabiosis animal model of APPswe/PS1dE9 (APP/PS1) transgenic (Tg) mice and wild-type (Wt) mice and the mice model of transplanting bone marrow cells (BMCs) from APP/PS1 Tg mice into Wt mice, the Aβ42 from Tg mice plasma or BMCs of Tg mice could significantly increase the plasma Aβ1−42 levels of Wt mice and enter into Wt mice brain to form cerebral amyloid angiopathy (CAA) and Aβ plaques similar to that of Tg mice brain [40, 41]. The present study employed three mouse models of AD to examine the effects of high plasma levels of Aβ1−42 on monocytes and macrophages.