. Co-occurrence of Alzheimer's disease ß-amyloid and τ pathologies at synapses. Neurobiol Aging. 2010 Jul;31(7):1145-52. PubMed.


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  1. My colleague and I would also like to echo the importance of the connection between amyloid, tau, and neuronal dysfunction. The concept that tau levels within the neuron dictate the toxic response to Aβ clearly works in both directions. Our lab, in conjunction with the Ferreira and Binder labs, showed that primary cultures (Rapoport et al., 2002) of tau knockout neurons were resistant to Aβ-induced cell death. These same tau knockout mice were mated to APP transgenics by Mucke’s lab and they also showed that loss of tau impairs amyloid mediated damage. It stands to reason, then, that increased intraneuronal levels of hyperphosphorylated tau would promote amyloid mediated neuronal damage. Our unique bigenic mouse models (APPSw/NOS2-/- and APPSwDI/NOS2-/-) clearly demonstrate that non-mutated mouse tau becomes hyperphosphorylated at AD-like sites in the presence of amyloid deposition. Furthermore, the increased levels of amyloid and hyperphosphorylated tau are associated with profound neuronal loss in multiple brain regions (Colton et al.; Wilcock et al.). In addition to this neuronal loss, the work by Gouras and colleagues suggest that colocalization of phospho-tau and amyloid may also affect synapses in a way that could further impair neuronal function. These intimate interconnections between tau, amyloid, synapses, and neuronal loss may be a critical starting point for the downward spiral observed in AD brains.


    . Progression of amyloid pathology to Alzheimer's disease pathology in an amyloid precursor protein transgenic mouse model by removal of nitric oxide synthase 2. J Neurosci. 2008 Feb 13;28(7):1537-45. PubMed.

    . NO synthase 2 (NOS2) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2006 Aug 22;103(34):12867-72. PubMed.

    . Tau is essential to beta -amyloid-induced neurotoxicity. Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6364-9. PubMed.

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  1. Aβ and Phospho-tau: Strange Bedfellows Get Intimate at Synapses