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, 107 (43), 18670-5

Early Deficits in Synaptic Mitochondria in an Alzheimer's Disease Mouse Model

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Early Deficits in Synaptic Mitochondria in an Alzheimer's Disease Mouse Model

Heng Du et al. Proc Natl Acad Sci U S A.

Abstract

Synaptic dysfunction and the loss of synapses are early pathological features of Alzheimer's disease (AD). Synapses are sites of high energy demand and extensive calcium fluctuations; accordingly, synaptic transmission requires high levels of ATP and constant calcium fluctuation. Thus, synaptic mitochondria are vital for maintenance of synaptic function and transmission through normal mitochondrial energy metabolism, distribution and trafficking, and through synaptic calcium modulation. To date, there has been no extensive analysis of alterations in synaptic mitochondria associated with amyloid pathology in an amyloid β (Aβ)-rich milieu. Here, we identified differences in mitochondrial properties and function of synaptic vs. nonsynaptic mitochondrial populations in the transgenic mouse brain, which overexpresses the human mutant form of amyloid precursor protein and Aβ. Compared with nonsynaptic mitochondria, synaptic mitochondria showed a greater degree of age-dependent accumulation of Aβ and mitochondrial alterations. The synaptic mitochondrial pool of Aβ was detected at an age as young as 4 mo, well before the onset of nonsynaptic mitochondrial and extensive extracellular Aβ accumulation. Aβ-insulted synaptic mitochondria revealed early deficits in mitochondrial function, as shown by increased mitochondrial permeability transition, decline in both respiratory function and activity of cytochrome c oxidase, and increased mitochondrial oxidative stress. Furthermore, a low concentration of Aβ (200 nM) significantly interfered with mitochondrial distribution and trafficking in axons. These results demonstrate that synaptic mitochondria, especially Aβ-rich synaptic mitochondria, are more susceptible to Aβ-induced damage, highlighting the central importance of synaptic mitochondrial dysfunction relevant to the development of synaptic degeneration in AD.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Increased accumulation of Aβ in synaptic mitochondria (mito) of Tg mAPP mice. (A and B) Age-related mitochondrial Aβ1-40 and Aβ1-42 accumulation in synaptic and nonsynaptic mitochondria from non-Tg and APP mice at 4 and 12 mo of age (n = 4–6 mice per group). *P < 0.05 vs. 4-mo-old Tg mAPP synaptic mitochondria; #P < 0.05 vs. 4-mo-old Tg mAPP nonsynaptic mitochondria. (C) Comparison of Aβ levels in synaptic mitochondria with those in nonsynaptic mitochondria from Tg mAPP mice at the age of 4 mo. (D–F) Immunogold EM images with a specific Aβ1-42 antibody, followed by a gold-conjugated antibody (18 nm), demonstrating the presence of intramitochondrial Aβ accumulation (black particles) in 12-mo-old Tg mAPP mice. Arrows denote mitochondria (M), and the asterisk denotes a synapse. (Scale bars = 200 nm.)
Fig. 2.
Fig. 2.
Mitochondrial RCRs of synaptic and nonsynaptic mitochondria from 4-mo-old non-Tg and Tg mAPP mice (n = 5–7 mice per group). *P < 0.05 vs. other mitochondrial fractions.
Fig. 3.
Fig. 3.
CypD expression level and Ca2+-induced mitochondrial swelling in Tg mAPP and non-Tg mice. (A) Age-dependent CypD expression in synaptic and nonsynaptic mitochondria from non-Tg and Tg mAPP mice at 4 and 12 mo of age. Data are expressed as fold increases compared with the CypD level in 4-mo-old non-Tg nonsynaptic mitochondria (n = 4–9 mice per group). (B) Mitochondrial swelling in synaptic (C1) and nonsynaptic (C2) mitochondria. Data are shown as percentages decreased from initial values (n = 5–9 mice per group). *P < 0.05 vs. 4-mo-old other mitochondrial fractions; #P < 0.05 vs. 4- and 12-mo-old non-Tg synaptic and Tg mAPP nonsynaptic mitochondria; §P < 0.05 vs. 4- and 12-mo-old non-Tg nonsynaptic mitochondria. Representative curves of the swelling in synaptic (C1) and nonsynaptic (C2) mitochondria are shown.
Fig. 4.
Fig. 4.
Accumulation of mitochondrial oxidative stress in Tg mice. (A) 4-HNE levels in synaptic and nonsynaptic mitochondria from the indicated Tg mice (n = 4–10 mice per group). *P < 0.05 vs. other mitochondrial fractions from 4-mo-old mice; ΔP < 0.05 vs. other 12-mo-old mitochondrial fractions; #P < 0.05 vs. 4-mo-old Tg mAPP nonsynaptic mitochondria; §P < 0.05 vs. 12-mo-old Tg mAPP nonsynaptic mitochondria. (B) Calcium-induced (1 mM) H2O2 production in synaptic and nonsynaptic mitochondria from the indicated Tg mice at 4 and 12 mo of age (n = 4–10 mice per group). *P < 0.05 vs. other 4-mo-old mitochondrial fractions; ΔP < 0.05 vs. other 12-mo-old mitochondrial fractions; #P < 0.05 vs. 4-mo-old Tg mAPP nonsynaptic mitochondria; §P < 0.05 vs. 12-mo-old Tg mAPP nonsynaptic mitochondria.
Fig. 5.
Fig. 5.
Effect of Aβ on mitochondrial distribution and trafficking in axons. (A) Axonal Mitochondrial Index (numbers per micron in axon) after Aβ1-42 (200 nM) treatment for 24 h on cultured hippocampal neurons. (A1) Data were collected from three independent experiments. *P < 0.05 vs. other groups. (A2) Representative images for vehicle- or Aβ-treated axonal mitochondrial distribution. Double-immunostaining with Mitotracker (red, mitochondrial marker) and Tau (green, axonal marker) was performed. (B) Axonal mitochondria trafficking in cultured non-Tg hippocampal neurons. Data were collected from 1,176, 546, and 563 mitochondria from vehicle, Aβ1-42, and Aβ42-1 groups, respectively, in four independent experiments. (B1) Percentages of stationary, moveable, anterograde-transported, and retrograde-transported mitochondria were compared with those of total mitochondria, respectively. (B2) Percentages of anterograde-transported and retrograde-transported mitochondria were compared with the total amount of movable mitochondria, respectively. *P < 0.05 vs. other groups. (C) Representative kymograph images of the vehicle and Aβ1-42–treated axonal mitochondrial movement. (Scale bars = 10 μm.) (D) Mitochondrial velocity. (D1) Average anterograde and retrograde transport velocity of movable mitochondria (μm/s) is shown. *P < 0.05 vs. other groups. Cumulative data for the anterograde transport velocity (D2) and retrograde transport velocity (D3) are shown. (E1) Average length of axonal mitochondria in micrometers. *P < 0.05 vs. other groups. (E2) Distribution of mitochondrial length.

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