The strong neurotropism of spirochetes is well known. Spirochetes can invade the brain and generate latent, persistent infection [29, 63, 65]. In addition to hematogenous dissemination, they can spread via the lymphatics and along nerve fiber tracts [63, 91]. Accordingly, periodontal invasive spirochetes were detected along the trigeminal nerve and in trigeminal ganglia . They might also propagate along the fila olfactoria and tractus olfactorius, which would be in harmony with the olfactory hypothesis [122–124] and with previous observations showing that the olfactory tract and bulb are affected in the earliest stages of the degenerative process in AD .
Spirochetes attach to host cells through their surface components, including collagen-binding proteins, bacterial amyloids and pore forming proteins [126–131]. Through activation of plasminogen and factor XII, bacterial amyloids contribute to inflammation and modulate blood coagulation .
The innate immune system enables host cells to recognize spirochetes, execute proinflammatory defenses, and start adaptive immune responses.
Pattern recognition receptors, located on the cell membrane of various cells, particularly on phagocytes and microglia recognize unique structures of spirochetes. The largest family of pattern recognition receptors is that of Toll-like receptors (TLRs). TLRs are also present in the brain . Macrophages and microglia activated through TLR signaling secrete chemokines and cytokines and express various proinflammatory molecules for the removal of pathogens and affected cells. Spirochetes and their surface lipoproteins activate TLR signaling through CD14 [134, 135]. As an example, tri- or di-acylated lipoproteins of B. burgdorferi bind to lipopolysaccharide binding protein (LBP), which activates TLR signaling through CD14 .
It is noteworthy, that in addition to spirochetal antigens and DNA, D-amino acids and bacterial peptidoglycan, two natural constituents of Prokaryotic cell wall unique to bacteria, were also detected in the brain in AD [83, 84, 137, 138]. Pattern recognition receptors are upregulated in the brain in AD, and TLR2 and TLR4 gene polymorphisms influence the pathology of AD [139, 140]. Activation of microglia with TLRs 2, 4 and 9 ligands markedly increases Aβ ingestion in vitro . Finally, stimulation of the immune system through TLR9 in AβPP (Tg2576) transgenic mice results in reduction of Aβ deposits .
Once microorganisms are recognized, the activation of the innate immune system induces phagocytosis and bacteriolysis through the formation of the membrane attack complex (MAC, C5b9) [143–145] and promotes inflammatory responses. Activation of the clotting cascade generates bradykinin, which increases vascular permeability. Spirochetes activate both the classic and alternative pathways and induce acute phase proteins. Serum amyloid A (SAA) and C Reactive Protein (CRP) levels are elevated in T. pallidum and B. burgdorferi infections [146, 147]. Through their ability to induce the production of tumor necrosis factor (TNF) by macrophages, spirochete lipoproteins play an important role in systemic and local inflammatory changes that characterize spirochetal infections .
In Alzheimer's disease, activated microglia that are designed to clean up bacteria and cellular debris surround senile plaques and extracellular neurofibrillary tangles . Both the cellular and humoral components of the immune system reactions [48–53] and critical constituents of the classical and alternative complement pathways are associated with AD lesions [51, 52, 149].
Spirochetes are able to evade host defense mechanisms and establish latent and slowly progressive chronic infection. They employ a broad range of strategies to overcome antigenic recognition, phagocytosis and complement lysis. Blockade of the complement cascade allows their survival and proliferation even in immune competent hosts. Complement resistant strains of B. burgdorferi possess five Complement Regulatory Acquiring Surface Proteins (CRASPS), which bind to factor H (FH) and factor-H like protein-1 (FHL-1) of the alternative pathway [145, 150]. Binding to the surface of spirochetes host FH and FHL-1 promotes the formation of inactive iC3b from C3b preventing MAC lysis. B. burgdorferi spirochetes possess a CD59-like complement inhibitory molecule as well , which by interacting with C8 and C9, inhibits binding of the opsonizing components C4b and C3b to MAC and consequently, prevents bacteriolysis . Impaired complement lysis was also observed in T. pallidum infection .
B. burgdorferi protects itself from destruction by the host adaptive immune system as well. It induces interleukin-12 (IL-12), a cytokine critical for driving cellular responses toward Th1 subset [152–154]. This shift retards antibody production by Th2 cells against the spirochete. Intracellular survival of spirochetes also confers protection against destruction by the host defense reactions. Evasion of spirochetes will result in their survival and proliferation in the brain. Their accumulation in the cerebral cortex will lead to the formation of senile plaques, tangles and granulovacuolar-like degeneration as shown by historic observations in syphilis [61, 62] and by current observations and in vitro experiments reviewed here (Fig. 7).
Accumulation in the brain of "paralytic iron" is characteristic in general paresis . Free iron abolishes the bactericidal effects of serum and strongly enhances bacterial virulence [155–157]. It is necessary for bacterial growth and plays a pivotal role in infection and inflammation [155–157]. Iron increases the formation of reactive oxygen intermediates causing lipid peroxidation and subsequent oxidative damage of proteins and nucleic acids [155–157]. Iron, also accumulates in the brain in AD [155, 158–160].
The production of reactive oxygen and nitrogen intermediates by innate immune cells is an effective host-defense mechanism against microbial pathogens. Activation of macrophages and other host cells by bacteria or LPS, including spirochetes and their lipoproteins generates substantial amount of nitric oxide (NO) , which is critical in bacterial clearance . Nitric oxide also plays a central role in AD .
Chronic bacterial infections (e.g. rheumatoid arthritis, leprosy, tuberculosis, syphilis, osteomyelitis) are frequently associated with amyloid deposition. Based on previous observations we have suggested that amyloidogenic proteins might be an integral part of spirochetes and could contribute to Aβ deposition in AD . Recent observations indeed showed that the BH (9-10) peptide of a beta-hairpin segment of B. burgdorferi outer surface protein A (OspA) forms amyloid fibrils in vitro, similar to human amyloidosis [163, 164]. Recent observations also show that amyloid proteins constitute a previously overlooked integral part of the cellular envelope of many bacteria [163–168]. Bacterial amyloids have important biological functions and contribute to bacterial virulence and invasion of host cells [165, 166].
Genetic mutations occurring in AD (AβPP, Presenilin 1 and 2) are related to the processing of AβPP and result in increased production of Aβ 1-42 and Aβ 1-43 . AβPP revealed to be a proteoglycan core protein  and is involved in the regulation of immune system responses and in T cell differentiation [171–173]. Recent observations showed that Aβ is an innate immune molecule and belongs to the family of antimicrobial peptides AMPs , which are involved in innate immune responses. Consequently, genetic defects in AβPP, PS-I and PS-II should be associated with an increased susceptibility to infection. ApoE4, an important risk factor for AD, is also risk factor for infection and enhances increased expression of inflammatory mediators [175, 176].
Promoter polymorphisms in pro-inflammatory cytokine genes facilitate infections . TNF-α plays a critical role in host defenses against infection [178, 179]. The influence of TNF-α on T. pallidum and B. burgdorferi infections has been repeatedly reported [153, 180]. Human Leukocyte Antigen (HLA) gene polymorphism is a dominant marker of susceptibility to infection, including B. burgdorferi infection . TNF-α and HLA polymorphisms, which are risk factors for infection, substantially influence the risk of AD as well [182–184].