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, 136 (5), 747-757

Region-specific Depletion of Synaptic Mitochondria in the Brains of Patients With Alzheimer's Disease

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Region-specific Depletion of Synaptic Mitochondria in the Brains of Patients With Alzheimer's Disease

Eleanor K Pickett et al. Acta Neuropathol.

Abstract

Of all of the neuropathological changes observed in Alzheimer's disease (AD), the loss of synapses correlates most strongly with cognitive decline. The precise mechanisms of synapse degeneration in AD remain unclear, although strong evidence indicates that pathological forms of both amyloid beta and tau contribute to synaptic dysfunction and loss. Synaptic mitochondria play a potentially important role in synapse degeneration in AD. Many studies in model systems indicate that amyloid beta and tau both impair mitochondrial function and impair transport of mitochondria to synapses. To date, much less is known about whether synaptic mitochondria are affected in human AD brain. Here, we used transmission electron microscopy to examine synapses and synaptic mitochondria in two cortical regions (BA41/42 and BA46) from eight AD and nine control cases. In this study, we observed 3000 synapses and find region-specific differences in synaptic mitochondria in AD cases compared to controls. In BA41/42, we observe a fourfold reduction in the proportion of presynaptic terminals that contain multiple mitochondria profiles in AD. We also observe ultrastructural changes including abnormal mitochondrial morphology, the presence of multivesicular bodies in synapses, and reduced synapse apposition length near plaques in AD. Together, our data show region-specific changes in synaptic mitochondria in AD and support the idea that the transport of mitochondria to presynaptic terminals or synaptic mitochondrial dynamics may be altered in AD.

Keywords: Alzheimer’s disease; Electron microscopy; Mitochondria; Synapses.

Figures

Fig. 1
Fig. 1
EM Sampling. TEM images were taken throughout the neuropil in a systematic fashion to ensure sampling from the entire tissue block face without repeated sampling or bias (a). Images were taken at ×6000 magnification (b). Individual synapses (inset in b, c) were identified by the presence of at least three presynaptic vesicles (red arrow) and a clearly identifiable, electron-dense post-synaptic density (blue arrow). The presence of mitochondria (m) in the pre- (shaded cyan) or post-(shaded magenta) synaptic terminals was recorded and the length of the PSD opposed to the presynaptic active zone was measured (green line). Scale bars represent 1 μm (b), 500 nm (c)
Fig. 2
Fig. 2
Examples of synapses and synaptic mitochondria. Mitochondria were observed both in presynaptic terminals (asterisks) and post-synaptic terminals (crosses) in control and AD subjects in BA41/42 (a, b) and BA46 (c, d). Scale bar 500 nm
Fig. 3
Fig. 3
Region-specific depletion of presynaptic mitochondria in AD. The percentage of presynaptic mitochondria is lower in BA41/42 than in BA46 (a, asterisk: two-way ANOVA effect of F (1, 26) = 5.965, p = 0.022). There were no differences in region or disease condition in the percentage of post-synaptic terminals containing mitochondria (b). Presynaptic terminals containing more than one mitochondria were over four times less common in presynaptic terminals of AD BA41/42 (c, asterisk: independent samples Kruskal–Wallis test, p = 0.004). Each data point shows the percentage for an individual case. Data are represented as mean and standard errors in a, b and medians with interquartile ranges (c, d)
Fig. 4
Fig. 4
Changes in synaptic morphology in AD. In control cases, multiple mitochondrial profiles in individual pre-synapses were observed (a, crosses), while in AD cases, mitochondria with irregular profiles were observed in synapses (b, asterisks). Multivesicular bodies (MVB, arrows, c) were observed in a subset of post-synapses, and occasional dark degenerating spines (§, c) were observed in AD cortex. MVB appeared most often in AD BA41/42 synapses where there was a trend to increase compared to control (d, Kruskal–Wallis, p = 0.06). Apposition length was unchanged in AD vs. controls in BA41/42 or BA46 (e). When more blocks were examined from temporal, frontal and occipital regions to find synapses near plaques (f, g) and the data combined, we observe significantly decreased apposition length in synapses near plaques compared to those far from plaques (f, asterisk: unpaired t test with Welch correction, t = 4.28, p = 0.01). g An example of a small synapse near a plaque. h More detail around a plaque including a synapses (with pre- and post-synaptic terminals labelled, the post-synapse contains a MVB), a dystrophic neurite, and a degenerating axon. Data are shown as median with interquartile range. Scale bars represent 500 nm (ac, inset g, h); 1000 nm (large panel g)
Fig. 5
Fig. 5
Fibrils in amyloid plaques and neurofibrillary tangles are observed in tissue from Alzheimer’s disease cases with TEM. Aβ plaques (P) surrounded by dystrophic neurites (D) and neuropil threads (NT) are detected in the neuropil from tissue derived from AD cases (a, b). NFT are observed around the soma of neurons from AD tissue (labeled T in c, d). Scale bar represents 2 μm in a, c, and d; 1 μm in b, inset 500 nm × 500 nm in b, 1000 × 1000 nm in d

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