Alzheimer's disease is characterized by senile (neuritic) plaques, neurofibrillary tangles, and loss of neural cells in the brain. In particular, β-amyloid deposited in senile plaques is considered to play a central role in the pathoetiology of Alzheimer's disease. β-Amyloid peptide (Aβ), the major component of β-amyloid deposits, is produced by metabolism of β-amyloid precursor protein (βAPP) by β- and γ-secretases in neural cells.
Alzheimer's disease is characterized by deposition in the brain of the 40-42-amino-acid Aβ peptide, which is proteolytically derived from amyloid precursor protein (APP), resulting in cerebral β-amyloid plaques (Selkoe, 2001, Physiol Rev. 81 (2):741-66). Despite low-level, chronic activation of innate immunity in Alzheimer's disease (Akiyama, et al. 2000, Neurobiol Aging. 21 (3):383-421), microglia, the brain's chief resident immune cells, ultimately do not clear β-amyloid deposits (Wisniewski et al., 1989, Can J Neurol Sci. 16 (4 Suppl):535-42).
It has been disclosed that the formation of senile plaques was suppressed and the number of existing senile plaques was reduced by administering Aβ peptide along with an adjuvant for immunization to transgenic mice which have pathological features of Alzheimer's disease and overexpress a human amyloid APP transgene (Schenk et al., 1999 Nature 400: 173-177).
Furthermore, it is known that the cytokine TGF-β1 (transforming growth factor β1) is overexpressed in brains of patients with Alzheimer's disease compared with healthy elderly and TGF-β1 promotes the production of inflammatory cytokines (IL-1β (interleukin-1β), TNF-α (tumor necrosis factor-α and the like) in vascular endothelial cells. Further, it has been reported that TGF-β1 promoted Alzheimer's disease-related pathological changes such as cerebrovascular amyloid deposition and microvascular degeneration (Wyss-Coray et al., 1997 Nature 389: 603-606; Wyss-Coray et al., 2000 Am. J. Pathol. 156: 139-150; Wyss-Coray et al., 2001 Nat. Med. 7: 612-618).
TGF-βs are pleiotropic cytokines with central roles in immune suppression, immune homeostasis and repair after injury (Li et al., 2006, Annu Rev Immunol. 24:99-146). TGF-β1 in brain dampens microglial activation (Brionne et al., 2003, Neuron. 40 (6):1133-45). However, TGF-β1 overexpression promotes brain inflammation (Wyss-Coray et al., 2000 Am J Pathol. 156 (1):139-50), simultaneously accelerates brain vascular β-amyloid deposits and reduces parenchymal β-amyloid deposits (Wyss-Coray et al., 1997, Nature 389: 603-6; Wyss-Coray, et al., 2001, Nat Med. 7 (5):612-8), and elicits neuronal Aβ secretion (Tesseur et al., 2006, J Clin Invest. 116 (10:3060-9).
Recent studies indicate that the relationship between microglial activation and promotion of AD-like pathology is not straightforward, as some forms of microglial activation appear to mitigate this pathology. It has been shown that immunization of the PDAPP mouse model of AD with Aβ1-42 results in marked reduction of Aβ deposits, and atypical punctate structures containing Aβ that resembled activated microglia were found in brains of these mice, suggesting that immunization activates microglia to phagocytose Aβ (Schenk et al., 1999 Nature 400: 173-7). This hypothesis was further supported ex vivo, where microglia were shown to clear deposited Aβ that was opsonized by anti-Aβ antibodies (Bard et al., 2000 Nat. Med. 6: 916-19). Similar prophylactic effects of Aβ1-42 immunization have now been independently observed in other transgenic mouse models of AD (Morgan et al., 2000 Nature 408: 982-5; Janus et al, 2000 Nature 408: 979-82), and in vivo visualization has shown that application of anti-Aβ antibody to PDAPP mouse brain results in rapid Aβ plaque clearance associated with marked local microglial activation (as measured by lectin immunoreactivity) (Bacskai et al., 2001 Nat. Med. 7: 369-72). In addition, bigenic mice that overexpress human APP and TGF-β1 also demonstrate reduced parenchymal Aβ deposition associated with an increase in microglia positive for the F4/80 antigen (Wyss-Coray et al., 2001 Nat. Med. 7: 612-18).
Therapeutic agents for Alzheimer's disease should be able to suppress senile plaque formation and amyloid deposition in the central nervous system and at the same time should not cause side effects such as encephalitis. Remediation of cerebral amyloidosis, including soluble and deposited forms of Aβ peptides, should prevent downstream pathological events as predicted by the “amyloid cascade hypothesis” of Alzheimer's disease (Hardy and Allsop, 1991 Trends Pharmacol. Sci. 12:383-388). There exists a need in the art to develop new medications for Alzheimer's disease.