While NFT accumulation is characteristic of Alzheimer’s disease (AD), several laboratories have reported that neuron loss and memory impairment are concurrent with accumulation of soluble species of tau and is dissociated from the accumulation of tangles in AD mouse models (Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, Maeda J, Suhara T, Trojanowski JQ, Lee VM. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007 53(3):337-51; Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, DeTure M, Ramsden M, McGowan E, Forster C, Yue M, Orne J, Janus C, Mariash A, Kuskowski M, Hyman B, Hutton M, Ashe KH. Tau suppression in a neurodegenerative mouse model improves memory function. Science. 2005 Jul 15; 309 (5733):476-81). Similarly, improvements in cognition in a mouse model producing tangles and plaques required immunological reduction of soluble tau protein, but not the insoluble tangles or plaques (Oddo S, Vasilevko V, Caccamo A, Kitazawa M, Cribbs DH, LaFerla FM. Reduction of soluble Abeta and tau, but not soluble Abeta alone, ameliorates cognitive decline in transgenic mice with plaques and tangles. J Biol Chem. 2006 Dec 22;281(51):39413-23.). The concept that soluble oligomers (small soluble aggregates) of amyloid proteins are the acutely toxic structures of these proteins, and not insoluble aggregates like plaques and tangles, has now become generally accepted for multiple neurodegenerative diseases (Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: leisons from the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol. 2007 Feb;8(2):101-12; Kayed, R., Thompson, H.E., McIntire T.M., Milton, S.C., Cotman, C.W., and Glabe, C.G. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science. 2003. 301, 1847-9).

There is a correlation between disease progression and the accumulation of granular tau oligomers in the brains of AD patients (Maeda S, Sahara N, Saito Y, Murayama S, Ikai A, Takashima A. Increased levels of granular tau oligomers: an early sign of brain aging and Alzheimer's disease. Neurosci Res. 2006. 54(3): 197-201). The soluble forms of tau correlating best with neuron loss and behavioral deficits are soluble oligomers (Berger Z, Roder H, Hanna A, Carlson A, Rangachari V, Yue M, Wszolek Z, Ashe K, Knight J, Dickson D, Andorfer C, Rosenberry TL, Lewis J, Hutton M, Janus C: Accumulation of pathological tau species and memory loss in a conditional model of tauopathy. J Neurosci. 2007 Apr 4; 27(14): 3650-62). It has been established that total levels of tau increase in the cerebrospinal fluid (CSF) of patients in AD (Sonnen JA, Keene CD, Montine KS, Li G, Peskind ER, Zhang J, Montine TJ. Biomarkers for Alzheimer's disease. Expert Rev Neurother. 2007 7(8):1021-8), and work at OLIGOMERIX has demonstrated that soluble tau oligomers are present in CSF and tend to accumulate in AD (unpublished results). Larger studies are being planned at OLIGOMERIX, working in collaboration with Columbia University with NIH funding for validation of this biomarker for AD. Soluble extracellular tau has been shown to promote neurotoxicity by interacting with specific receptors on the surface of neurons (Gómez-Ramos A, Díaz-Hernández M, Rubio A, Miras-Portugal MT, Avila J. Extracellular tau promotes intracellular calcium increase through M1 and M3 muscarinic receptors in neuronal cells. Mol Cell Neurosci. 2008 In Press) suggesting a mechanism by which tau oligomers in the CSF may impair memory and cause neurotoxicity.

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