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Interaction between NH(2)-tau fragment and Abeta in Alzheimer's disease mitochondria contributes to the synaptic deterioration.

Authors: Amadoro, G  Corsetti, V  Atlante, A  Florenzano, F  Capsoni, S  Bussani, R  Mercanti, D  Calissano, P 
Citation: Amadoro G, etal., Neurobiol Aging. 2012 Apr;33(4):833.e1-25. doi: 10.1016/j.neurobiolaging.2011.08.001. Epub 2011 Sep 29.
Pubmed: (View Article at PubMed) PMID:21958963
DOI: Full-text: DOI:10.1016/j.neurobiolaging.2011.08.001

Although amyloid beta (Abeta) peptide can promote tau pathology and its toxicity is concurrently tau-dependent, the underlying mechanisms of the in vivo interplay of these proteins remain unsolved. Structural and functional mitochondrial alterations play an early, precipitating role in synaptic failure of Alzheimer's disease (AD) pathogenesis and an aggravated mitochondrial impairment has been described in triple APP/PS/tau transgenic mice carrying both plaques and tangles, if compared with mice overexpressing tau or amyloid precursor protein (APP) alone. Here, we show that a neurotoxic aminoterminal (NH(2))-derived tau fragment mapping between 26 and 230 amino acids of the human tau40 isoform (441 amino acids)-but not the physiological full-length protein-preferentially interacts with Abeta peptide(s) in human AD synapses in association with mitochondrial adenine nucleotide translocator-1 (ANT-1) and cyclophilin D. The two peptides-Abeta 1-42 and the smaller and more potent NH(2)-26-44 peptide of the longest 20-22 kDa NH(2)-tau fragment-inhibit the ANT-1-dependent adenosine diphosphate-adenosine triphosphate (ADP/ATP) exchange in a noncompetitive and competitive manner, respectively, and together further aggravate the mitochondrial dysfunction by exacerbating the ANT-1 impairment. Taken together, these data establish a common, direct and synergistic toxicity of pathological APP and tau products on synaptic mitochondria and suggest potential, new pathway(s) and target(s) for a combined, more efficient therapeutic intervention of early synaptic dysfunction in AD.

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CRRD Object Information
CRRD ID: 9681463
Created: 2014-12-02
Species: All species
Last Modified: 2014-12-02
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.