Astroglial tracer BU99008 detects multiple binding sites in Alzheimer\u2019s disease brain

Amit Kumar,Bernardino Ghetti,Mona-Lisa Malarte,Agneta Nordberg,Niina A Koistinen,Inger Nennesmo,Martin Ingelsson,Laetitia Lemoine

doi:10.1038/s41380-021-01101-5

Abstract

With reactive astrogliosis being established as one of the hallmarks of Alzheimer’s disease (AD), there is high interest in developing novel positron emission tomography (PET) tracers to detect early astrocyte reactivity. BU99008, a novel astrocytic PET ligand targeting imidazoline-2 binding sites (I2BS) on astrocytes, might be a suitable candidate. Here we demonstrate for the first time that BU99008 could visualise reactive astrogliosis in postmortem AD brains and propose a multiple binding site [Super-high-affinity (SH), High-affinity (HA) and Low-affinity (LA)] model for BU99008, I2BS specific ligands (2-BFI and BU224) and deprenyl in AD and control (CN) brains. The proportion (%) and affinities of these sites varied significantly between the BU99008, 2-BFI, BU224 and deprenyl in AD and CN brains. Regional binding studies demonstrated significantly higher 3H-BU99008 binding in AD brain regions compared to CN. Comparative autoradiography studies reinforced these findings, showing higher specific binding for 3H-BU99008 than 3H-Deprenyl in sporadic AD brain compared to CN, implying that they might have different targets. The data clearly shows that BU99008 could detect I2BS expressing reactive astrocytes with good selectivity and specificity and hence be a potential attractive clinical astrocytic PET tracer for gaining further insight into the role of reactive astrogliosis in AD.

Highlights

Amyloid plaques, neurofibrillary tangles and neuroinflammatory markers such as aberrant astrocytes and microglia are considered to play an important role in the pathophysiological processes characterising the development of Alzheimer’s disease (AD)
To further characterise 3H-BU99008 tracer binding properties, competition binding studies were performed with different concentrations of the unlabelled imidazoline-2 binding sites (I2BS) specific ligands BU99008, 2-BFI and BU224
Astrocytes are the main homeostatic cells in the CNS. They are highly heterogenous and can be further sub-classified into different types based on their regional distribution in the brain, for example, fibrous and velate astrocytes of the white matter and cerebellum, respectively [54]. They can undergo disease-specific modifications and complex neuropathological changes such as astrodegeneration and pathological remodelling, that can further evolve with the disease progression, in addition to reactive astrogliosis [54]

Summary

Introduction

Neurofibrillary tangles and neuroinflammatory markers such as aberrant astrocytes and microglia are considered to play an important role in the pathophysiological processes characterising the development of Alzheimer’s disease (AD). The human brain has an average of 50% of glial cells, but in the cerebral cortex, they account for 80% of the cells, whereas in the cerebellum, glia cells account for around 20% [6] They play a crucial role in regulating homeostasis of glutamate and γ-aminobutyric acid (GABA) transport through glutamate/GABA-glutamine shuttle [4, 7, 8] and can induce synaptic plasticity and boost memory formation, as recently demonstrated [9, 10]. Most importantly, they respond to CNS insults/injuries and disease state by a specific defense process called reactive astrogliosis [11, 12]. Reactive astrocytes can undergo morphological changes and upregulate the production of glial fibrillary acidic proteins (GFAP) [11] and promote the release of inflammatory mediators such as cytokines (interleukin (IL)1b and IL-6) and tumour necrosis factor-alpha [22], thereby triggering/promoting neuroinflammation as observed in AD [16, 17, 23, 24]

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