Imaging of Peripheral Benzodiazepine Receptor Expression as Biomarkers of Detrimental versus Beneficial Glial Responses in Mouse Models of Alzheimer's and Other CNS Pathologies

Abstract

We demonstrate the significance of peripheral benzodiazepine receptor (PBR) imaging in living mouse models of Alzheimer's disease (AD) as biomarkers and functional signatures of glial activation. By radiochemically and immunohistochemically analyzing murine models of the two pathological hallmarks of AD, we found that AD-like A␤ deposition is concurrent with astrocyte-dominant PBR expression, in striking contrast with nonastroglial PBR upregulation in accumulations of AD-like phosphorylated tau. Because tauinduced massive neuronal loss was distinct from the marginal neurodegeneration associated with A␤ plaques in these models, cellular localization of PBR reflected deleterious and beneficial glial reactions to tau versus A␤ pathologies, respectively. This notion was subsequently examined in models of various non-AD neuropathologies, revealing the following reactive glial dynamics underlying differential PBR upregulation: (1) PBR(Ϫ) astrogliosis uncoupled with microgliosis or coupled with PBR(ϩ) microgliosis associated with irreversible neuronal insults; and (2) PBR(ϩ) astrogliosis coupled with PBR(Ϫ or Ϯ) microgliosis associated with minimal or reversible neuronal toxicity. Intracranial transplantation of microglia also indicated that nontoxic microglia drives astroglial PBR expression. Moreover, levels of glial cell line-derived neurotrophic factor (GDNF) in astrocytes were correlated with astroglial PBR, except for increased GDNF in PBR(-) astrocytes in the model of AD-like tau pathology, thereby suggesting that PBR upregulation in astrocytes is an indicator of neurotrophic support. Together, PBR expressions in astrocytes and microglia reflect beneficial and deleterious glial reactions, respectively, in diverse neurodegenerative disorders including AD, pointing to new applications of PBR imaging for monitoring the impact of gliosis on the pathogenesis and treatment of AD.

Central Nervous System Expression and PET Imaging of the Translocator Protein in Relapsing–Remitting Experimental Autoimmune Encephalomyelitis

“…In vitro and in vivo analyses with the SPECT TSPO ligand 123 I-CLINDE (26)(27)(28) confirmed literature data indicating that the TSPO is expressed during neuroinflammation (14) and indicated that 123 I-CLINDE is a sensitive and specific tracer of astroglial activation.…”

“…Consequently, it has been suggested that TSPO functions may be important in modulating neuronal damage (12) and hence may support accelerated microglial proliferation. Furthermore, because TSPO expression in healthy subjects is not detectable, quantitative PET imaging provides an excellent opportunity to image the early symptoms of diseases through the use of radiotracers that target the TSPO (13)(14)(15).…”

Multimodal Imaging for DREADD-Expressing Neurons in Living Brain and Their Application to Implantation of iPSC-Derived Neural Progenitors

“…Implantations of neural progenitor cells prepared from hM4Di-iPSCs and DsRed-iPSCs into the brains of WT mice were conducted as described previously (Ji et al, 2008). Briefly, male WT C57BL/6J mice (12-24 weeks old) were anesthetized with 1.5% (v/v) isoflurane and placed in a stereotactic frame (Narishige).…”

Reactive Astrocytes Overexpress TSPO and Are Detected by TSPO Positron Emission Tomography Imaging

“…It is generally admitted that reactive microglia are responsible for the signal observed with TSPO radioligands (Venneti et al, 2006;Chauveau et al, 2008Chauveau et al, , 2009. However, an original study reported that astrocytes overexpress TSPO (Kuhlmann and Guilarte, 2000), and others have suggested their potential contribution to the TSPO PET signal (Rojas et al, 2007;Ji et al, 2008). The major limitation of PET studies exploring TSPO expression is the animal model used (intracerebral injection of neurotoxins, ischemia, transgenic mice) or the clinical disease considered.…”