Article

Reducing Endogenous Tau Ameliorates Amyloid -Induced Deficits in an Alzheimer's Disease Mouse Model

Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
Science (Impact Factor: 33.61). 06/2007; 316(5825):750-4. DOI: 10.1126/science.1141736
Source: PubMed

ABSTRACT

Many potential treatments for Alzheimer's disease target amyloid-beta peptides (Abeta), which are widely presumed to cause the disease. The microtubule-associated protein tau is also involved in the disease, but it is unclear whether treatments aimed at tau could block Abeta-induced cognitive impairments. Here, we found that reducing endogenous tau levels prevented behavioral deficits in transgenic mice expressing human amyloid precursor protein, without altering their high Abeta levels. Tau reduction also protected both transgenic and nontransgenic mice against excitotoxicity. Thus, tau reduction can block Abeta- and excitotoxin-induced neuronal dysfunction and may represent an effective strategy for treating Alzheimer's disease and related conditions.

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    • "Taken together, these findings suggest that caspases play a pivotal role in appoptosininduced neurodegeneration and that caspase inhibition may be a potential target in the treatment of neurodegenerative disorders in instances where interference with caspase-dependent synaptic function is less consequential in comparison to overall ameliorative effects in disease onset with caspase inhibition. It was previously shown that tau plays an essential role in Ab-induced behavioral deficits, dendritic and axonal abnormalities in AD mouse models, and neuronal cultures (Ittner et al., 2010; Roberson et al., 2007; Stancu et al., 2014; Vossel et al., 2010). "
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    • "The derivation and characterization of PDAPP-J20 [hAPP(J20)] mice has been described elsewhere (Hsia et al., 1999; Mucke et al., 2000; Selkoe, 2000; Galvan et al., 2006; Roberson et al., 2007; Beauquis et al., 2014). This strain, a recognized model of AD, carries the hAPP gene with the familial AD Swedish and Indiana mutations, develops amyloid pathology and behavioral alterations in a progressive fashion (Galvan et al., 2006), and also shows evidence of Tau hyperphosphorylation (Simon et al., 2009). "
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    • "First, tau-deficient neurons have been shown to be resistant to Aβ-mediated neurotoxicity (Rapoport et al., 2002). Second, genetic deficiency of tau in an AD mouse model improved cognitive function and reduced excitotoxic injury (Roberson et al., 2007; Ittner et al., 2010). Third, Shipton and colleagues recently showed that deficiency of tau protected against Aβ-induced impairment of long-term potentiation in hippocampal slices of wild type mice (Shipton et al., 2011). "
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