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. 2011 Sep;122(3):285-92.
doi: 10.1007/s00401-011-0843-x. Epub 2011 Jun 1.

Postsynaptic degeneration as revealed by PSD-95 reduction occurs after advanced Aβ and tau pathology in transgenic mouse models of Alzheimer's disease

Charles Y Shao  1 , Suzanne S Mirra, Hameetha B R Sait, Todd C Sacktor, Einar M Sigurdsson
Affiliations

Postsynaptic degeneration as revealed by PSD-95 reduction occurs after advanced Aβ and tau pathology in transgenic mouse models of Alzheimer's disease

Charles Y Shao et al. Acta Neuropathol. 2011 Sep.

Abstract

Impairment of synaptic plasticity underlies memory dysfunction in Alzheimer's disease (AD). Molecules involved in this plasticity such as PSD-95, a major postsynaptic scaffold protein at excitatory synapses, may play an important role in AD pathogenesis. We examined the distribution of PSD-95 in transgenic mice of amyloidopathy (5XFAD) and tauopathy (JNPL3) as well as in AD brains using double-labeling immunofluorescence and confocal microscopy. In wild type control mice, PSD-95 primarily labeled neuropil with distinct distribution in hippocampal apical dendrites. In 3-month-old 5XFAD mice, PSD-95 distribution was similar to that of wild type mice despite significant Aβ deposition. However, in 6-month-old 5XFAD mice, PSD-95 immunoreactivity in apical dendrites markedly decreased and prominent immunoreactivity was noted in neuronal soma in CA1 neurons. Similarly, PSD-95 immunoreactivity disappeared from apical dendrites and accumulated in neuronal soma in 14-month-old, but not in 3-month-old, JNPL3 mice. In AD brains, PSD-95 accumulated in Hirano bodies in hippocampal neurons. Our findings support the notion that either Aβ or tau can induce reduction of PSD-95 in excitatory synapses in hippocampus. Furthermore, this PSD-95 reduction is not an early event but occurs as the pathologies advance. Thus, the time-dependent PSD-95 reduction from synapses and accumulation in neuronal soma in transgenic mice and Hirano bodies in AD may mark postsynaptic degeneration that underlies long-term functional deficits.

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Figures

Figure 1
Figure 1. PSD-95 decreases in apical dendrites in 6 month old, but not in 3 month old, 5XFAD mice
a. PSD-95 (green) and Aβ (red) immunoreactivity with TO-PRO 3 (blue) nuclear counterstain in hippocampus of wild type (WT), 3 month old (3M) and 6 month old (6M) 5XFAD mice. PSD-95 immunoreactivity highlights regions of apical dendrites in CA1, CA3 and DG (dentate gyrus). Boxes indicate the portion of CA1 region illustrated in b and c. Bar for all = 500 μm. b. High power images show PSD-95 and Aβ double labeling. PSD-95 immunoreactivity is prominent in apical dendrites and weak in soma in WT. Similar PSD-95 distribution is seen in 3M 5XFAD, despite of the presence of Aβ plaques. In contrast, PSD-95 immunoreactivity is weak in apical dendrites and prominent in soma (arrow) in 6M 5XFAD. Bar for all = 50 μm. c. Images of 100 μm × 100 μm areas show TO-PRO 3 stained nuclei (upper panel) and PSD-95 labeled apical dendrites (lower panel) that were analyzed in d and e respectively. Bar for all = 50 μm. d. Numbers of neuronal nuclei counted in CA1 pyramidal layer do not differ among the 3 groups: WT = 24.0±0.4; 3M = 23.5 ±0.5; 6M = 23.0±0.6 (p > 0.05, ANOVA). e. PSD-95 intensity measured in CA1 apical dendrites is reduced in 6M 5XFAD by 39.6±1.3% and 41.8±1.4% compared with WT and 3M 5XFAD mice, respectively (*: p < 0.001, post hoc Tukey test).
Figure 2
Figure 2. PSD-95 decreases in apical dendrites in hippocampus in 14 month old, but not in 3 month old, JNPL3 mice
a. PSD-95 (green) and tau (red) immunoreactivity with TO-PRO 3 (blue) nuclear counterstain in hippocampus of wild type (WT), 3 month old (3M) and 14 month old (14M) JNPL3 mice. Boxes indicate the portion of CA1 region illustrated in b and c. Bar for all = 500 μm. b. High power images show PSD-95 and tau double-labeling. In WT, PSD-95 immunoreactivity labels apical dendrites and no tau positive neurons are present. In 3M JNPL3, PSD-95 immunoreactivity also labels apical dendrites, with a number of tau positive neurons present. In 14M JNPL3, PSD-95 immunoreactivity disappears from apical dendrites and appears in a number of neuronal soma (arrow), some of which localize with tau (arrowhead). Bar for all = 50 μm. c. Images of 100 μm × 100 μm areas show TO-PRO 3 stained nuclei (upper panel) and PSD-95 labeled apical dendrites (lower panel) that were analyzed in d and e respectively. Bar for all = 50 μm. d. Numbers of neuronal nuclei counted from CA1 pyramidal layer do not differ among the 3 groups: WT = 24.2±0.7, 3M = 23.6 ±0.3, 14M = 23.2±0.2 (p > 0.05, ANOVA). e. PSD-95 intensity measured from CA1 apical dendrites is significantly reduced in 14M by 57.7±0.9% and 57.4±5.1% compared to WT and 3M JNPL3 mice, respectively (*: p < 0.001, post hoc Tukey test).
Fig. 3
Fig. 3. PSD-95 immunoreactivity in Hirano bodies in AD brains
a. PSD-95 (green) and tau (red) immunoreactivity with TO-PRO 3 counterstain (blue) in CA1 region of a control brain. PSD-95 immunoreactivity labels neuropil, while no tau positivity is detected. b. CA1 region of an AD brain shows tau positive neurofibrillary tangles (NFT, arrowhead) and dystrophic neurons (DN) and PSD-95 positive spindle-like Hirano bodies (HB, arrows). c. H&E stain shows an eosinophilic HB (arrow) in association with a neuron. b. A HB (arrow) is labeled with PSD-95 antibody with immunoproxidase-DAB reaction. e. A HB (arrow) is double-labeled with antibodies to PSD-95 and MAP2, a somatodendritic marker. f. A HB (arrow) is double-labeled with antibodies to PSD-95 and actin filament. Bar in b for a and b = 50 μm. Bar in f for c, d, e, and f = 20μm.
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