The role of the adaptive immune response
The role of the adaptive immune response in AD is not fully understood and previous studies are controversial. In this context, serum levels of T and B lymphocytes were found to be reduced in AD patients, suggesting a decline of the immune response during the course of the disease (Richartz-Salzburger et al., 2007). However, in transgenic mice overexpressing APP, ablation of T and Dasatinib Monohydrate sale reduce both Aβ levels and the pathology in the brain, suggesting that lymphocytes are involved in the pathogenic mechanisms (Spani et al., 2015). In addition, T lymphocytes are involved in Aβ clearance in healthy individuals, albeit being less responsive to APP peptides in AD patients (Trieb et al., 1996). In the CNS, microglial cells are considered to be the main component of the innate immune response and are important antigen-presenting cells (APC). Activated microglia can acquire M1 inflammatory profile and secrete several inflammatory mediators, such as pro-inflammatory cytokines and reactive oxygen species (ROS) (Heneka, 2014). On its surface, microglia expresses many molecules, including receptors for neurotransmitters, hormones, cytokines and chemokines, toll-like receptors (TLRs) 2, 4 and 6, and major histocompatibility complex (MHC) molecules (Rigato et al., 2011, Parkhurst et al., 2013). In AD, Aβ can interact with different microglial receptors, which induces activation of microglia to a highly inflammatory state (Bamberger et al., 2003) and phagocytosis of the Aβ peptide (El Khoury et al., 1996, Bamberger et al., 2003, Stewart et al., 2010). In early stages of the disease, an increased expression of microglial activation markers, such as MHC II, CD40 and inducible nitric oxide synthase (iNOS), is observed in the hippocampus of animals; and both microglial and astroglial activation markers are highly expressed in Aβ-burdened neurons (Ferretti et al., 2012, Hanzel et al., 2014). Taken together, these observations indicate a protective role of microglia in early stages of AD (Hickman et al., 2008, Krabbe et al., 2013). On the other hand, the massive accumulation around senile plaques (Cras et al., 1990) during the progress of the disease suggests the microglial inability to process the excess of the Aβ peptide. Microglial cells may also contribute to the neurodegeneration through the production and release of pro-inflammatory cytokines, neurotoxins and other products. These molecules inhibit the expression of Aβ-binding receptors and the activity of enzymes that process Aβ (Giovannini et al., 2002, Hickman et al., 2008, Krabbe et al., 2013). Moreover, activation of microglia associated with complement-dependent pathway may contribute to early synapse loss (Hong et al., 2016). Additionally, microglia is also activated by tau (de Calignon et al., 2012), and both in vitro and in vivo microglia depletion significantly reduces tau spreading through the inhibition of exocytosis of this protein (Asai et al., 2015). Astrocytes, the most abundant cells in the brain, perform various functions, including physical and physiological support for the cerebral neuronal circuits (Khakh and Sofroniew, 2015). They also express pattern recognition receptors, such as TLR2, 3 and 4, which may be regulated by inflammatory factors (Hamby et al., 2012, Holm et al., 2012, Zamanian et al., 2012). Similar to microglia, astrocytes play an essential role in Aβ degradation (Wyss-Coray et al., 2003), despite being associated with deposits of Aβ accumulation even in early stages of AD. In this context, a study with individuals carrying autosomal dominant AD showed that astrocytosis occurs previously or concurrently with the fibrillary Aβ deposition stage (Scholl et al., 2015). In a similar study, longitudinal multitracer positron emission tomography assessment revealed prominent astrocytosis about 17 years before the expected onset of symptoms and cognitive decline of AD, accompanying the increase in Aβ accumulation during the disease progression (Rodriguez-Vieitez et al., 2016).