FDG-PET shows that microglial activation might drive cerebral glucose uptake in mice and patients with AD.

Progressive supranuclear palsy (PSP), initially described by Steele et al,¹ is a primary 4-repeat tauopathy² clinically characterized by postural instability with falls and impaired volitional eye movements and leading to death with a median of 8 years after symptom onset.² However, clinical symptoms and subtypes of PSP also have strong overlaps with other neurodegenerative disorders such as TDP-43–positive frontotemporal dementia or corticobasal degeneration.^3,4 Thus, clinical assessments in PSP are lacking sensitivity early in the disease course and have a limited specificity for the pathologic entity.⁵ Therefore, biomarkers for PSP have a great range of potential utility, for which formal criteria are now available.⁶ Current PSP diagnosis criteria already take imaging of atrophy or hypometabolism by magnetic resonance imaging or positron emission tomography (PET) into account.⁵ However, no available biomarker currently fulfills the criteria for an ideal biomarker, which would be positive in a presymptomatic stage, specific for any variant of pathology, and anticipate disease progression.⁶ As more established readouts (hypometabolism, atrophy) represent late events in the disease course, tau-PET imaging may be able to provide more favorable biomarker information for early detection of PSP. Other tau-PET tracers were reported to be able to differentiate patients with PSP from controls,^7-9 but the observed binding was not confirmed to specifically relate to tau.^10-12 The novel tau-PET tracer ¹⁸F-PI-2620 proved absent off-target binding to monoamine oxidases,¹³ high affinity to 3/4R tau in Alzheimer disease (AD),¹⁴ but also high affinity to recombinant 4R tau fibrils and PSP brain homogenate,¹³ and colocalized binding to proven 4R tau by a combination of micro-autoradiography and immunohistochemistry in PSP tissue.¹³

Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer’s disease (AD), suggesting that activation of this innate immune receptor may be a useful therapeutic strategy. Here we describe a high-affinity human TREM2-activating antibody engineered with a monovalent transferrin receptor (TfR) binding site, termed antibody transport vehicle (ATV), to facilitate blood–brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced signaling compared to a standard anti-TREM2 antibody. In human induced pluripotent stem cell (iPSC)-derived microglia, ATV:TREM2 induced proliferation and improved mitochondrial metabolism. Single-cell RNA sequencing and morphometry revealed that ATV:TREM2 shifted microglia to metabolically responsive states, which were distinct from those induced by amyloid pathology. In an AD mouse model, ATV:TREM2 boosted brain microglial activity and glucose metabolism. Thus, ATV:TREM2 represents a promising approach to improve microglial function and treat brain hypometabolism found in patients with AD.

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder associated with a loss of dopaminergic (DA) neurons. Despite symptomatic therapies, there is currently no disease-modifying treatment to halt neuronal loss in PD. A major hurdle for developing and testing such curative therapies results from the fact that most DA neurons are already lost at the time of the clinical diagnosis, rendering them inaccessible to therapy. Understanding the early pathological changes that precede Lewy body pathology (LBP) and cell loss in PD will likely support the identification of novel diagnostic and therapeutic strategies and help to differentiate LBP-dependent and -independent alterations. Several previous studies identified such specific molecular and cellular changes that occur prior to the appearance of Lewy bodies (LBs) in DA neurons, but a concise map of such early disease events is currently missing. Methods: Here, we conducted a literature review to identify and discuss the results of previous studies that investigated cases with incidental Lewy body disease (iLBD), a presumed pathological precursor of PD. Results: Collectively, our review demonstrates numerous cellular and molecular neuropathological changes occurring prior to the appearance of LBs in DA neurons. Conclusions: Our review provides the reader with a summary of early pathological events in PD that may support the identification of novel therapeutic and diagnostic targets and aid to the development of disease-modifying strategies in PD.

Amyloid imaging by small animal PET (µPET) in models of Alzheimer’s disease (AD) offers the possibility to track amyloidogenesis and brain energy metabolism. Since microglial activation is thought to contribute to AD pathology, we undertook a triple tracer µPET study to assess microglia activation and glucose metabolism in association with amyloid plaque load in a transgenic AD mouse model. Methods: Groups of PS2APP and C57Bl/6 wild-type (WT) mice of various ages were examined by µPET. We acquired 90 min dynamic emission data with ¹⁸F-GE180 for imaging activated microglia (18kD translocator protein ligand, TSPO), and static 30-60 min recordings with ¹⁸F-FDG for energy metabolism and ¹⁸F-florbetaben for amyloidosis. Optimal fusion of PET data was obtained through automatic non-linear spatial normalization, and standardized-uptake-value-ratios (SUVR) were calculated. For the novel TSPO tracer ¹⁸F-GE180, we then calculated distribution volume ratios (DVR) after establishing a suitable reference region. Immunohistochemical analyses with TSPO antisera, methoxy-X04 staining for fibrillary β-amyloid, and ex vivo autoradiography served as terminal gold standard assessments. Results: SUVR at 60-90 min p.i. gave robust quantitation of ¹⁸F-GE180, which correlated well with DVR calculated from the entire recording, and using a white matter reference region. Relative to age-matched WT, ¹⁸F-GE180 SUVR was slightly elevated in PS2APP mice at five months (+9%; p<0.01), and distinctly increased at 16 months (+25%; p<0.001). Over this age range, there was high positive correlation between µPET findings of microglial activation with amyloid load (R=0.85; p<0.001), and likewise with metabolism (R=0.61; p<0.005). Immunohistochemical and autoradiographic findings confirmed the in vivo µPET data. Conclusion: In this first triple tracer µPET in a well-established AD mouse model, we find evidence for age-dependent microglia activation. This activation, correlating positively with the amyloid-load, implies a relationship between amyloidosis and inflammation in the PS2APP AD mouse model.

Background: Genetic mutations underlying familial Alzheimer’s disease (AD) were identified decades ago, but the field is still in search of transformative therapies for patients. While mouse models based on overexpression of mutated transgenes have yielded key insights in mechanisms of disease, those models are subject to artifacts, including random genetic integration of the transgene, ectopic expression and non-physiological protein levels. The genetic engineering of novel mouse models using knock-in approaches addresses some of those limitations. With mounting evidence of the role played by microglia in AD, high-dimensional approaches to phenotype microglia in those models are critical to refine our understanding of the immune response in the brain. Methods: We engineered a novel App knock-in mouse model (App^SAA) using homologous recombination to introduce three disease-causing coding mutations (Swedish, Arctic and Austrian) to the mouse App gene. Amyloid-β pathology, neurodegeneration, glial responses, brain metabolism and behavioral phenotypes were characterized in heterozygous and homozygous App^SAA mice at different ages in brain and/ or biofluids. Wild type littermate mice were used as experimental controls. We used in situ imaging technologies to define the whole-brain distribution of amyloid plaques and compare it to other AD mouse models and human brain pathology. To further explore the microglial response to AD relevant pathology, we isolated microglia with fibrillar Aβ content from the brain and performed transcriptomics and metabolomics analyses and in vivo brain imaging to measure energy metabolism and microglial response. Finally, we also characterized the mice in various behavioral assays. Results: Leveraging multi-omics approaches, we discovered profound alteration of diverse lipids and metabolites as well as an exacerbated disease-associated transcriptomic response in microglia with high intracellular Aβ content. The App^SAA knock-in mouse model recapitulates key pathological features of AD such as a progressive accumulation of parenchymal amyloid plaques and vascular amyloid deposits, altered astroglial and microglial responses and elevation of CSF markers of neurodegeneration. Those observations were associated with increased TSPO and FDG-PET brain signals and a hyperactivity phenotype as the animals aged. Discussion: Our findings demonstrate that fibrillar Aβ in microglia is associated with lipid dyshomeostasis consistent with lysosomal dysfunction and foam cell phenotypes as well as profound immuno-metabolic perturbations, opening new avenues to further investigate metabolic pathways at play in microglia responding to AD-relevant pathogenesis. The in-depth characterization of pathological hallmarks of AD in this novel and open-access mouse model should serve as a resource for the scientific community to investigate disease-relevant biology.