TSPO ligand PK11195 improves Alzheimer-related outcomes in aged female 3xTg-AD mice

Abstract

Alzheimer's disease (AD) pathogenesis is a multifactorial process that involves numerous pathways within the central nervous system. Thus, interventions that interact with several disease-related pathways may offer an increased opportunity for successful prevention and treatment of AD. Translocator protein 18 kD (TSPO) is a mitochondrial protein that is associated with regulation of many cellular processes including inflammation, steroid synthesis, apoptosis, and mitochondrial respiration. Although TSPO ligands have been shown to be protective in several neurodegenerative paradigms, little work has been done to assess their potential as treatments for AD. Female 3xTg-AD mice were administered the TSPO ligand PK11195 once weekly for 5 weeks beginning at 16 months, an age characterized by extensive β-amyloid pathology and behavioral impairments. Animals treated with PK11195 showed improvements in behavior and modest reductions of in both soluble and deposited β-amyloid. The finding that short-term PK11195 treatment was effective in improving both behavioral and pathological outcomes in a model of late-stage AD supports further investigation of TSPO ligands as potential therapeutics for the treatment of AD.

Keywords: Aging; Alzheimer’s; Neuroinflammation; TSPO; β-Amyloid.

Fig 1.

The TSPO ligand PK11195 improves behavioral outcomes. (A) Aged female 3xTg-AD mice spent significantly more time in the open arms of the elevated plus maze after treatment with PK11195. (B) In the spontaneous alternation task, PK11195 was associated with a significant increase in correct alternations, (C) but no significant difference in the number of total arm entries in the Y-maze; N=6–7. * indicates p < 0.05 relative to Vehicle group.

Fig 2.

Quantitative immunohistochemistry shows effects of PK11195 treatment on β-amyloid deposition in the hippocampus. Representative images show β-amyloid immunostaining in the subiculum of (A) vehicle and (B) PK11195-treated animals. Scale bar = 100 µm. (C) Quantification of β-amyloid load shows significant reduction associated with PK11195 treatment (filled bars) in the subiculum, but not in CA1 or CA2/3 regions of the hippocampus; N=6–7 (D) TBS soluble Aβ42 was not significantly different between vehicle- and PK11195-treated mice. (E) Detergent soluble Aβ42 was significantly decreased by PK11195 treatment; N=4–5. * indicates p < 0.05 relative to Vehicle group.

Fig 3.

Quantitative PCR data show effects of PK11195 treatment on mRNA expression of microglial and inflammatory markers. Data show mean (+SEM) relative expression levels in hippocampus of the macrophage/microglial markers (A) CD11b and (B) F4/80, and the pro-inflammatory cytokines (C) IL-6 and (D) IL-1β in Vehicle (open bars) and PK11195 treated (filled bars) mice; N=6–7. * indicates p < 0.05 relative to Vehicle group.