Lipopolysaccharide (LPS)-induced neuroinflammation
A commonly studied model of neuroinflammation is LPS-induced neuroinflammation which represents the current standard paradigm to study neuroinflammation both
in vivo [
42,
43] and
in vitro [
26,
44]. LPS, also known as endotoxin, is a component of the outer membrane of gram-negative bacteria. LPS binds CD14 on microglia membranes. The LPS-CD14 complex then interacts with the toll-like receptor-4 (TLR-4) [
26,
45], which, in turn, activates microglia by initiating signal transduction cascades leading to rapid transcription and release of pro-inflammatory cytokines [
46] (including IL-1, IL-6, IL-12, p40, and TNF-α), chemokines (for example, CCL2, CCL5, and CXCL8), the complement system proteins (for example, C3, C3a, and C5a receptors) [
46], as well as anti-inflammatory cytokines like IL-10 [
47] and transforming growth factor-β (TGF-β) [
48].
Different paradigms of LPS-induced neuroinflammation exist with respect to the route of administration, duration of exposure and age of the animals [
49]. While chronic central administration of LPS can induce memory and learning deficits analogous to AD cognitive decline [
50], systemic LPS administration led to selective hippocampal impairment in context-object discrimination but not spatial memory [
51]. Moreover, Bordou and colleagues recently investigated the role of duration of exposure to LPS as well as the age of exposed rats on the neuroinflammatory response to LPS. Male rats at three age groups of young (3 months), middle-aged (9 months), and aged (23 months) received continuous infusion of picomolar levels of LPS (or artificial CSF as control) into their fourth ventricle [
49]. The duration of exposure was either 3 or 8 weeks. Among all cytokines, TNF-α increase in response to LPS infusion was similar in different age groups [
49]. However, in contrast to young rats, IL-1β did not significantly increase after 3 weeks of infusion in middle-aged and aged rats. Instead, aged rats had significantly increased IFN-γ compared with younger rats [
49]. Among rats of the same age group, longer duration of exposure to LPS infusion significantly increased the elevations of IL-1-α, IL-2, IL-4, IL-5, IL-6, IL-12, IL-13, and GM-CSF levels [
49]. This study provides an evidence of the influence of age and chronicity of infection on neuroinflammatory responses in certain regions of the brain, like locus coeruleus, which undergo significant cell loss in early stages of AD [
52].
In similar studies performed by Wenk and coworkers [
43,
53-
55], chronic neuroinflammation was modeled through continuous infusion of picomolar concentrations of LPS into the fourth ventricle of adult rats. A widespread activation of microglia was detected 2 days after the initiation of LPS infusion [
55]. Within 2 weeks after the cessation of LPS infusion, microglial activation decreased in most brain areas barring the hippocampus, and after the following 2 weeks, inflammation was mainly localized in the hippocampus [
55]. Furthermore, MRI scans showed shrinkage of the temporal lobe and enlargement of the lateral ventricles. Of note, electron microscopic studies showed impaired protein synthesis in hippocampal neurons of LPS-injected animals [
54]. Moreover, neuronal loss and impairment of long-term potentiation were reported in the entorhinal cortex [
56] and the dentate gyrus of the hippocampus respectively [
57], altogether explaining the decline in spatial memory [
56]. In this model, LPS-induced neuroinflammation was time dependent (maximal within 4 weeks of infusion) as well as cell and region specific (microglia in hippocampus) [
55].
Other groups have provided evidence of exacerbated AD-related protein pathology such as increased Aβ production through enhanced β-secretase activity in APP sweTg [
44] and tau hyperphosphorylation in 3xTg-AD mice following LPS injection [
42]. However, wild-type animals injected with LPS showed no increased Aβ deposition in the time course of 3 months. The authors argue that this process might occur at a later time point due to severe neuronal dysfunction and neurodegeneration [
44]. Another explanation for the lack of Aβ deposition in LPS-injected animals was proposed by DiCarlo et al. by showing a reduction of established Aβ plaques after intrahippocampal LPS injection through stimulation of Aβ clearance [
58].
In line with neurodegenerative structural changes, LPS-induced neuroinflammation caused cognitive deficits leading to impaired performance in associative and spatial learning tasks [
59,
60]. Finally, a long-term characterization of LPS-induced changes with regard to the chronology of histological and ultrastructural changes, as well as cognitive deficits, is required to assess the compatibility of LPS neuroinflammation model with the inflammation hypothesis of AD [
13].