Interaction between NH(2)-tau fragment and A? in Alzheimer's disease mitochondria contributes to the synaptic deterioration.
Although amyloid beta (A?) 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 A? peptide(s) in human AD synapses in association with mitochondrial adenine nucleotide translocator-1 (ANT-1) and cyclophilin D. The two peptides-A? 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.
Mesh Terms:
Adenine Nucleotide Translocator 1, Adenosine Diphosphate, Adenosine Triphosphate, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Analysis of Variance, Animals, Animals, Newborn, Apoptosis, Brain, Cells, Cultured, Cerebellum, Cyclophilins, Disks Large Homolog 4 Protein, Enzyme Inhibitors, Female, Humans, Immunoprecipitation, Intracellular Signaling Peptides and Proteins, Lewy Body Disease, Male, Membrane Proteins, Middle Aged, Mitochondria, Neuroblastoma, Neurons, Parkinson Disease, Peptide Fragments, Rats, Rats, Wistar, Receptors, AMPA, Staurosporine, Subcellular Fractions, Synapses, Synaptosomes, tau Proteins
Adenine Nucleotide Translocator 1, Adenosine Diphosphate, Adenosine Triphosphate, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Analysis of Variance, Animals, Animals, Newborn, Apoptosis, Brain, Cells, Cultured, Cerebellum, Cyclophilins, Disks Large Homolog 4 Protein, Enzyme Inhibitors, Female, Humans, Immunoprecipitation, Intracellular Signaling Peptides and Proteins, Lewy Body Disease, Male, Membrane Proteins, Middle Aged, Mitochondria, Neuroblastoma, Neurons, Parkinson Disease, Peptide Fragments, Rats, Rats, Wistar, Receptors, AMPA, Staurosporine, Subcellular Fractions, Synapses, Synaptosomes, tau Proteins
Neurobiol. Aging
Date: Apr. 01, 2012
PubMed ID: 21958963
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