Tau protein is found primarily associated with axons in differentiated neurons where it functions to stabilize microtubule structure and regulate transport. However, during Alzheimer’s disease (AD) and other tauopathies tau loses its normal function and gains toxic activity. Tau protein aggregates and is sequestered into filaments and higher order neurofibrillary tangles (NFT), a pathological hallmark of AD, and is modified by multiple mechanisms (Ballatore C et al. Nat Rev Neurosci. 2007 8:663-72). Studies using mouse models of AD and tauopathies show a strong correlation between the accumulation of soluble oligomeric species of tau and neuronal loss and memory impairment (Berger Z et al. J Neurosci. 2007 27:3650-62; Brunden KR et al. J Alzheimers Dis. 2008 14:393-9), and have challenged the assumption that NFT are the neurotoxic structures of tau. As AD progresses, tau pathology reproducibly spreads through the hippocampal structure to the cortex in a contiguous, highly selective and orderly fashion (Braak, H. and E. Braak. J Neural Transm Suppl, 1998. 53:127-40; Schönheit B et al. Neurobiol Aging. 2004 25:697-711) suggesting that aberrant tau protein may be involved in transmitting pathology to neighboring neurons during disease progression. Tau pathology may be transmitted to neighboring healthy neurons through muscarinic receptors I and III (Gómez-Ramos A et al. Eur Neuropsychopharmacol. 2009 19:708-17) or by directly entering cells and functioning as a template for intracellular tau to misfold, aggregate and cause neurodegeneration (Clavaguera F et al. Nat Cell Biol. 2009 11:909-13; Frost B et al. J Biol Chem. 2009 284:12845-52). In AD the levels of extracellular tau increase in cerebrospinal fluid, presumably due to release of intracellular proteins during cell death; hence its use as a biomarker for AD (Trojanowski JQ et al. Alzheimers Dement. 2010 6:230-8). Tau secretion to the extracellular space and to postsynaptic neurons was shown to be dependent on the N-terminus of tau and tauopathy mutations facilitating tau aggregation (Kim W et al. J Alzheimers Dis. 2010 19:647-64). Here, we show that extracellular tau oligomers have a causative effect on disrupting memory in studies of synaptic function in hippocampal slices and behavior in mice. Extracellular tau oligomers, but not monomeric tau, reduced long-term potentiation (LTP) (IC50 5 nM) and impaired associative fear memory in normal mice. These results strongly support extracellular tau oligomers as a target for drug discovery for AD and related tauopathies.

Validation of extracellular tau oligomer target for drug discovery in a novel animal model

PUZZO, DANIELA;
2010

Abstract

Tau protein is found primarily associated with axons in differentiated neurons where it functions to stabilize microtubule structure and regulate transport. However, during Alzheimer’s disease (AD) and other tauopathies tau loses its normal function and gains toxic activity. Tau protein aggregates and is sequestered into filaments and higher order neurofibrillary tangles (NFT), a pathological hallmark of AD, and is modified by multiple mechanisms (Ballatore C et al. Nat Rev Neurosci. 2007 8:663-72). Studies using mouse models of AD and tauopathies show a strong correlation between the accumulation of soluble oligomeric species of tau and neuronal loss and memory impairment (Berger Z et al. J Neurosci. 2007 27:3650-62; Brunden KR et al. J Alzheimers Dis. 2008 14:393-9), and have challenged the assumption that NFT are the neurotoxic structures of tau. As AD progresses, tau pathology reproducibly spreads through the hippocampal structure to the cortex in a contiguous, highly selective and orderly fashion (Braak, H. and E. Braak. J Neural Transm Suppl, 1998. 53:127-40; Schönheit B et al. Neurobiol Aging. 2004 25:697-711) suggesting that aberrant tau protein may be involved in transmitting pathology to neighboring neurons during disease progression. Tau pathology may be transmitted to neighboring healthy neurons through muscarinic receptors I and III (Gómez-Ramos A et al. Eur Neuropsychopharmacol. 2009 19:708-17) or by directly entering cells and functioning as a template for intracellular tau to misfold, aggregate and cause neurodegeneration (Clavaguera F et al. Nat Cell Biol. 2009 11:909-13; Frost B et al. J Biol Chem. 2009 284:12845-52). In AD the levels of extracellular tau increase in cerebrospinal fluid, presumably due to release of intracellular proteins during cell death; hence its use as a biomarker for AD (Trojanowski JQ et al. Alzheimers Dement. 2010 6:230-8). Tau secretion to the extracellular space and to postsynaptic neurons was shown to be dependent on the N-terminus of tau and tauopathy mutations facilitating tau aggregation (Kim W et al. J Alzheimers Dis. 2010 19:647-64). Here, we show that extracellular tau oligomers have a causative effect on disrupting memory in studies of synaptic function in hippocampal slices and behavior in mice. Extracellular tau oligomers, but not monomeric tau, reduced long-term potentiation (LTP) (IC50 5 nM) and impaired associative fear memory in normal mice. These results strongly support extracellular tau oligomers as a target for drug discovery for AD and related tauopathies.
Tau oligomer ; Drug Discovery; memory
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.11769/74867
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