**2.10 Toll-like receptors**

*Neuroprotection - New Approaches and Prospects*

**2.9 Cholesterol receptors**

potential mechanism of neurodegeneration in AD. Therefore, blocking NMDAR receptor-mediated glutaminergic neurotransmission can decrease cytotoxicity, thereby preventing further damage to neurons and cellular oxidative damage [22]. Therefore, NMDAR antagonists have emerged as potential compounds for AD patients since the receptor itself has many subunits and its variants have several brain functions. For example, conantokine acts as an NMDA receptor antagonist and plays an important role in understanding the importance of NMDA receptor inhibition in the AD treatment. Moreover, NMDAR activation might be blocked by an AD drug, memantine, an NMDAR antagonist which selectively blocks the function of extra synaptic NMDARs, but does not affect normal neurotransmission. However, memantine (and other current medications used to treat AD) only relieve

Regarding cholesterol receptors, some specific genotypes have been related to a higher or lower risk of dementia and AD. Even genotypes associated with AD neuropathology attenuation could be associated with late-onset of dementia. Liver nuclear X receptors (LXRs) are the main regulators of cholesterol homeostasis and CNS inflammation. The brain, which contains about 25% of total body cholesterol, requires a complex and balanced cholesterol metabolism to maintain neuronal function. Deregulation of cholesterol metabolism has been implicated in several neurodegenerative diseases, including AD. Due to their anti-inflammatory activities, LXRs play a crucial role in CNS function. Although LXR agonists have therapeutic potential in neurological diseases, the use of LXR in these pathologies remains problematic. The recent discovery of cholesterol derivatives which function as LXR agonists has shown new roles for LXRs in midbrain neurogenesis. Elucidating the repertoire of endogenous ligands for LXR will improve the under-

Nuclear X receptor signaling affects AD development through various pathways. Studies indicate that LXR genetic loss in transgenic mice results in increased amyloid plaques. Studies also suggest that LXRs activation in mice improves the expression of cholesterol efflux-linked genes (ApoE and ABCA-1), induces APP processing, and reduces Aß synthesis, with significant improvement in memory. Furthermore, LXR agonists have also been shown to inhibit neuroinflammation by modulating microglial phagocytosis and repressing COX2, MCP1, and INOS expression in glial cells [25]. The T allele of NR1H2 (rs2695121) presents the most significant risk for AD among all LXR-β gene polymorphisms. Taken together, these findings suggest that brain-penetrable LXR agonists or LXR modulators may be

Additionally, chromosome 12p has been recognized as an AD-associated region.

This chromosome includes genes for LDL receptor 1 (LRP1) and oxidized lowdensity lipoprotein receptor 1 (OLR1). OLR1 is a class E scavenger receptor and is a transmembrane glycoprotein. In vitro factors such as oxidized LDL, oxidative stress, and inflammatory cytokines, as well as in vivo factors such as diabetes mellitus, hyperlipidemia, and hypertension, may induce OLR1 expression. Increased oxidized LDL levels induce endothelial cell activation and dysfunction, apoptosis, and impaired vessel relaxation, thus contributing to atherosclerosis development and progression through OLR1. Epidemiological and clinical literature has reported an association between atherosclerosis, vascular risk factors, and AD. Therefore, ORL1 variations may lead to low efficiency in the oxidized LDL removal and therefore increased Aβ levels, which may result in neuronal death. Indeed, a single nucleotide polymorphism in OLR1 located in the 3′ untranslated region of the gene

the symptoms and do not alter the disease progression [23].

standing of how this receptor regulates CNS lipid metabolism [24].

useful therapeutic agents for AD treatment and prevention [26].

**110**

Toll-like receptors (TLRs) are innate immune system receptors which are activated by pathogens (PAMP) or damage-associated molecular patterns (DAMPs). Toll-like receptors are associated with neuronal injury in chronic inflammatory conditions but also with functional recovery after nerve injury. Amyloid aggregates seem to be a type of DAMP and may interact and activate standard recognition receptors. Two TLR actions (ligand binding and immune signaling) may have beneficial effects on AD pathology. Moreover, microglial activation represents an important AD hallmark. Analysis of genetic polymorphisms suggested relationships between TLR polymorphisms and AD risk, further supporting the hypothesis that TLRs are involved in AD [28]. In fact, TLR2 is elevated in the hippocampus and cortex of AD patients and mice. In this context, it was observed that a TLR2 binding peptide (WT TIDM) inhibited Aβ-induced microglial activation, reduced Aβ load, attenuated neuronal apoptosis, and improved memory and learning in mice. However, WT TIDM peptide was not effective in TLR2 knockout mice [29].

Importantly, TLR5 binds to APP with high-affinity, forming complexes which block APP toxicity. In turn, APP fibrils modulate the human TLR5 activation via flagellin, but APP cannot activate TLR5 signaling by themselves. Thus, TLR5-related biological data suggest this receptor as a potential agent in AD therapy [30]. A new TLR9 signaling pathway has recently been associated with the immune-inflammatory response, reducing Aβ levels in AD mice. Therefore, TLR9 may represent a functional candidate gene for AD [31]. Moreover, TLR4 has also been described in the brain and seems to regulate some physiological processes such as neurogenesis. In this sense, TLR4 plays an important role during neurodegenerative disorders. PRDX6 has been shown to inhibit neural stem cell neurogenesis by down-regulating the TLR4 signaling pathway [32]. An early TLR3-mediated signal improves Aβ neuronal autophagy, although it increases neuronal apoptosis in the late stage of AD. Similarly, TLR7, TLR8, and TLR9 may improve early Aβ microglial uptake, but over time, they contribute to neuroinflammation. Therefore, TLRs, in particular TLR2 and TLR4, represent suitable targets for therapeutic intervention in AD and carefully targeting them may increase Aβ autophagy and phagocytosis, as well as reduce inflammatory responses. Several modulators with selective TLR agonist or antagonist activity have been developed, and many of them could produce a therapeutic benefit in AD patients [33].
