Caspase-Cleaved Tau Impairs Mitochondrial Dynamics in Alzheimer’ s Disease María José Pérez 1 & Katiana Vergara-Pulgar 1 & Claudia Jara 1 & Fabian Cabezas-Opazo 1 & Rodrigo A. Quintanilla 1,2 Received: 28 September 2016 /Accepted: 4 January 2017 # Springer Science+Business Media New York 2017 Abstract Alzheimer’ s disease (AD) is characterized by the presence of aggregates of tau protein. Tau truncated by caspase-3 (D421) or tau hyperphosphorylated at Ser396/S404 might play a role in the pathogenesis of AD. Mitochondria are dynamic organelles that modify their size and function through mitochondrial dynamics. Recent studies have shown that alter- ations of mitochondrial dynamics affect synaptic communica- tion. Therefore, we studied the effects of pathological forms of tau on the regulation of mitochondrial dynamics. We used pri- mary cortical neurons from tau( -/-) knockout mice and immor- talized cortical neurons (CN1.4) that were transfected with plas- mids containing green fluorescent protein (GFP) or GFP with different tau forms: full-length (GFP-T4), truncated (GFP- T4C3), pseudophosphorylated (GFP-T42EC), or both truncated and pseudophosphorylated modifications of tau (GFP-T4C3- 2EC). Cells expressing truncated tau showed fragmented mito- chondria compared to cells that expressed full-length tau. These findings were corroborated using primary neurons from tau( -/ -) knockout mice that expressed the truncated and both truncated and pseudophosphorylated forms of tau. Interestingly, mitochon- drial fragmentation was accompanied by a significant reduction in levels of optic atrophy protein 1 (Opa1) in cells expressing the truncated form of tau. In addition, treatment with low concentra- tions of amyloid-beta (Aβ) significantly reduced mitochondrial membrane potential, cell viability, and mitochondrial length in cortical cells and primary neurons from tau(-/-) mice that ex- press truncated tau. These results indicate that the presence of tau pathology impairs mitochondrial dynamics by reducing Opa1 levels, an event that could lead to mitochondrial impairment observed in AD. Keywords Tau . Mitochondria . Alzheimer’ s disease . Neurodegeneration . Opa1 Introduction Alzheimer’ s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia in the elderly [1]. AD is characterized by the accumulation of extracellular senile plaques formed by deposits of amyloid-beta (Aβ) peptide and the presence of intracellular aggregates known as neurofi- brillary tangles (NFTs), which are formed by pathological forms of the tau protein [1]. These protein aggregates are neurotoxic and are responsible for synaptic dysfunction, mitochondrial dam- age, oxidative stress, and ultimately death of significant numbers of neurons in the hippocampus and cerebral cortex [2–5]. Tau is a microtubule-associated protein which is mainly expressed in axons [6–8], where it regulates vesicular and mitochondrial trans- port [9]. Post-translational modifications such as abnormal phos- phorylation and cleavage of tau are considered hallmarks of AD [10, 11]. Modifications such as tau hyperphosphorylation at ser- ine 396 (S396) and serine 404 (S404) and tau truncation or cleavage by caspase-3 (D421) have been detected in AD brains [12]. Interestingly, previous studies from our group and others María José Pérez and Katiana Vergara-Pulgar contributed equally to this work. Electronic supplementary material The online version of this article (doi:10.1007/s12035-017-0385-x) contains supplementary material, which is available to authorized users. * Rodrigo A. Quintanilla rodrigo.quintanilla@uautonoma.cl 1 Laboratory of Neurodegenerative Diseases, Centro de Investigación Biomédica, Universidad Autónoma de Chile, El Llano Subercaseaux 2801 5to Piso, San Miguel, 8910000 Santiago, Chile 2 Centro de Investigación y Estudio del Consumo de Alcohol en Adolescentes (CIAA), Santiago, Chile Mol Neurobiol DOI 10.1007/s12035-017-0385-x