Ligand for translocator protein reverses pathology in a mouse model of Alzheimer's disease - PubMed (original) (raw)

Ligand for translocator protein reverses pathology in a mouse model of Alzheimer's disease

Anna M Barron et al. J Neurosci. 2013.

Abstract

Ligands of the translocator protein (TSPO) elicit pleiotropic neuroprotective effects that represent emerging treatment strategies for several neurodegenerative conditions. To investigate the potential of TSPO as a therapeutic target for Alzheimer's disease (AD), the current study assessed the effects of the TSPO ligand Ro5-4864 on the development of neuropathology in 3xTgAD mice. The effects of the TSPO ligand on neurosteroidogenesis and AD-related neuropathology, including β-amyloid accumulation, gliosis, and behavioral impairment, were examined under both early intervention (7-month-old young-adult male mice with low pathology) and treatment (24-month-old, aged male mice with advanced neuropathology) conditions. Ro5-4864 treatment not only effectively attenuated development of neuropathology and behavioral impairment in young-adult mice but also reversed these indices in aged 3xTgAD mice. Reduced levels of soluble β-amyloid were also observed by the combination of TSPO ligands Ro5-4864 and PK11195 in nontransgenic mice. These findings suggest that TSPO is a promising target for the development of pleiotropic treatment strategies for the management of AD.

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Figures

Figure 1.

Figure 1.

Ro5-4864 reduces Aβ accumulation in the hippocampus of 3xTgAD mice. A–J, Representative photomicrographs show Aβ immunoreactivity in hippocampus CA1 (A–E) and subiculum (F–J) regions of 7-month-old 3xTgAD mice in the sham + vehicle (A, F), GDX + vehicle (B, G), and GDX + Ro5-4864 (C, H) conditions; and 24-month-old 3xTgAD mice administered vehicle (D, I) and Ro5-4864 (E, J). Data show mean Aβ immunoreactivity loads (±SEM) in 3xTgAD mice at ages 7 months (solid bars, left axis) and 24 months (open bars, right axis) in hippocampus CA1 (K) and subiculum (L). *p < 0.05, compared with all other groups.

Figure 2.

Figure 2.

Ro5-4864 reduces hippocampal gliosis in 3xTgAD mice. A–J, Representative photomicrographs show GFAP (A–E) and IBA-1 (F–J) immunoreactivities in the hippocampus CA1 region of 7-month-old 3xTgAD mice in the sham + vehicle (A, F), GDX + vehicle (B, G), and GDX + Ro5-4864 (C, H) conditions; and 24-month-old 3xTgAD mice administered vehicle (D, I) and Ro5-4864 (E, J). K, GFAP immunoreactivity volume density values (±SEM) in the hippocampus CA1 region. L, IBA-1 immunoreactivity volume density values (±SEM) in the hippocampus CA1 region. #p < 0.001, compared with GDX + vehicle. *p < 0.001, compared with all other groups.

Figure 3.

Figure 3.

Ro5-4864 regulates brain testosterone and progesterone levels and improves behavioral deficits in 3xTgAD mice. A, Brain testosterone levels were quantified in limbic structures. Ro5-4864 treatment attenuated GDX-induced testosterone depletion in young-adult 7-month-old mice. B, Brain progesterone levels were quantified in limbic structures. Ro5-4864 treatment increased PROG more than twofold in GDX 7-month-old mice. C, Percentage duration (±SEM) spent exploring the open arm of the EPM, with increased exploration of the open arm indicative of reduced anxiety. D, SAB, represented as percentage alternation (±SEM); both 7-month-old GDX and 24-month-old 3xTgAD mice administered Ro5-4864 exhibited significantly improved SAB performance. #p < 0.05, compared with sham + vehicle. *p < 0.05, compared with all other groups.

Figure 4.

Figure 4.

Ro5-4864 alone or in combination with PK-11195 reduces brain Aβ levels in non-Tg mice. Brain levels of soluble AβX-40 (A) and AβX-42 (B) from hemibrain homogenates were assessed by ELISA in young-adult non-Tg mice treated for 4 weeks with vehicle, Ro5-4864, PK11195, or Ro5-4864 + PK11195. Data are mean ± SEM. *p < 0.02, compared with GDX + vehicle. ‡p < 0.001, compared with GDX + vehicle.

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