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, 179 (4), 2071-82

Tau Accumulation Causes Mitochondrial Distribution Deficits in Neurons in a Mouse Model of Tauopathy and in Human Alzheimer's Disease Brain

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Tau Accumulation Causes Mitochondrial Distribution Deficits in Neurons in a Mouse Model of Tauopathy and in Human Alzheimer's Disease Brain

Katherine J Kopeikina et al. Am J Pathol.

Abstract

Neurofibrillary tangles (NFT), intracellular inclusions of abnormal fibrillar forms of microtubule associated protein tau, accumulate in Alzheimer's disease (AD) and other tauopathies and are believed to cause neuronal dysfunction, but the mechanism of tau-mediated toxicity are uncertain. Tau overexpression in cell culture impairs localization and trafficking of organelles. Here we tested the hypothesis that, in the intact brain, changes in mitochondrial distribution occur secondary to pathological changes in tau. Array tomography, a high-resolution imaging technique, was used to examine mitochondria in the reversible transgenic (rTg)4510, a regulatable transgenic, mouse model and AD brain tissue. Mitochondrial distribution is progressively disrupted with age in rTg4510 brain, particularly in somata and neurites containing Alz50-positive tau aggregates. Suppression of soluble tau expression with doxycycline resulted in complete recovery of mitochondrial distribution, despite the continued presence of aggregated tau. The effect on mitochondrial distribution occurs without concomitant alterations in neuropil mitochondrial size, as assessed by both array tomography and electron microscopy. Similar mitochondrial localization alterations were also observed in human AD tissue in Alz50+ neurons, confirming the relevance of tau to mitochondrial trafficking observed in this animal model. Because abnormalities reverted to normal if soluble tau was suppressed in rTg4510 mice, even in the continued presence of fibrillar tau inclusions, we suggest that soluble tau plays an important role in mitochondrial abnormalities, which likely contribute to neuronal dysfunction in AD.

Figures

Figure 1
Figure 1
Three-dimensional analysis of mitochondrial content of neurons using array tomography. Z-stack projections of 99 sequential 80-nm array tomography images of an Alz50+ cell (A) and a nearby Alz50− cell (B) from rTg4510 brain exhibits the perinuclear localization of mitochondria (VDAC/porin) in Alz50− cells which appears reduced in Alz50+ cells. Panels C and D show partial 3-dimensional reconstructions through the same cells, the cytoplasm of which are encircled by the white lines. Scale bars = 5 μm.
Figure 2
Figure 2
Mitochondrial distribution is disrupted in 5.5-month-old rTg4510 neurons. Array tomography images of single 70-nm sections from layer II/III of somatosensory cortex in rTg4510 were used to analyze percent area occupied by mitochondria (stained with VDAC/porin – green) within the soma (A) and neurites (B) (identified with tubulin staining – white outlines). Scale bars: 10 μm (A); 5 μm (B). Quantification reveals that soma with Alz50+ tau accumulations (red) have depleted mitochondrial fraction (C) and neurites both with and without pathological tau accumulations have altered mitochondrial distribution (D). *P < 0.0001, **P < 0.05.
Figure 3
Figure 3
rTg4510 neurons at 8.5 months of age have disrupted mitochondrial distribution, which can be ameliorated with transgene suppression. Box and whisker plots demonstrate percent cytoplasm occupied by mitochondria in soma (A) and neurites (B) of both untreated and doxycycline-treated 8.5-month-old rTg4510 and nonTg mice. As with the younger age group, neurites in the rTg4510, regardless of whether or not tau aggregates are present, are depleted of mitochondrial content whereas somatic mitochondrial distribution is only impacted with the presence of aggregated tau. In addition, 6 weeks of doxycycline treatment allows for recovery of mitochondrial distribution to near that of nonTg levels in both the somata and neurites. Representative array tomography images of mitochondrial distribution in single 70-nm sections of untreated 8.5-month-old rTg4510 (C) and doxycycline-treated 8.5-month-old rTg4510 (D) exhibit depletion of somatic mitochondrial content in Alz50+ cells, indicated by the arrow in C, whereas the arrowhead in D indicates recovery to near control levels following 6 weeks of doxycycline treatment. *P < 0.0001, **P < 0.005, and ***P < 0.0001. Scale bars = 10 μm.
Figure 4
Figure 4
Mitochondrial volume is maintained even in the presence of distribution deficits. Three-dimensional volume reconstructions (A) of 8 × 70 nm sections immunofluorescently stained for VDAC in 8.5-month-old nonTg (left) and Tg4510 (right) mice were used to measure volumes of individual mitochondria in the neuropil. These volume measurements were verified by comparison with volumes estimated from cross-sectional measurements of mitochondria on electron microscopy images (B). Each mitochondrion was measured at its widest and longest points as demonstrated with lines within the mitochondria beside the arrows. An ellipsoidal volume approximation was calculated from these diameters. Mitochondrial volumes approximated from electron micrographs confirmed the mitochondrial volumes obtained with the automated output of the array tomography method. Quantification of array volumes of n = 3922 mitochondria demonstrated no significant differences in volumes of individual mitochondria of the neuropil (C) between 8.5-month-old Tg4510 and nonTg mice (depicted as medians with SD). Scale bar = 2 μm.
Figure 5
Figure 5
Somatic mitochondrial distribution is disrupted in neurons in human AD brain. Array tomography images of single 70-nm sections from human control (CTL) (A) and human AD brain (B) reveal mitochondrial distribution is altered in both Alz50+ and Alz50− neurons compared with control brain (quantified in C). *P < 0.0001. Scale bars = 10 μm.

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