While astrocytes normally help fight β-amyloid plaque deposition, sustained astrocyte reactivity could lead to astrocyte dystrophy, gray matter atrophy, and glucose hypometabolism.
In this new study, scientists Nicholas R Livingston, Paul Edison and their colleagues at Imperial College, London, used the new imidazoline receptor 11C-BU99008 PET tracer to test the hypothesis of a dynamic relationship between the reactivity of astrocytes and neurodegeneration.
They found evidence of increased astrocyte reactivity in patients with pathologically developed amyloid plaques, mainly in the frontal, parietal and occipital regions. These increases were greater in patients with mild cognitive impairment than in patients with Alzheimer's disease.
Further analyzes showed that the lower reactivity of astrocytes in patients with pathologically developed amyloid plaques was associated with both hypometabolism of glucose in the parietal, temporal and frontal lobes and gray matter atrophy in the frontal and temporal lobes.
However, greater deposition of β-amyloid plaques was associated with increased reactivity of astrocytes in primary cortical motor and sensory areas, but decreased reactivity of astrocytes in temporal regions.
11C-BU99008 is a novel PET tracer that binds to I2-BS, the expression of which is associated with the reactivity of astrocytes. There are three main classes of imidazoline receptors: I1 is involved in inhibiting the sympathetic nervous system to lower blood pressure, I2 has functions as yet unclear but is involved in several psychiatric disorders, and I3 regulates insulin secretion. The I2-BS protein located in the brain, is upregulated with healthy aging, and is further increased in Alzheimer's disease.
Different past studies have reinforced the hypothesis that astrocyte reactivity is an early event in the progression of Alzheimer's disease pathology, occurring in response to early amyloid deposition, which usually originates in the frontal lobe. In the early stages, reactive astrocytes have a neuroprotective role, aiding in the clearance of β-amyloid plaques.
In the cohort studied by the scientists, they found weaker binding of 11C-BU99008 in the temporal lobe, which was associated with greater relative progression of amyloid-associated neuropathology, i.e. glucose hypometabolism and gray matter atrophy. Scientists propose that this reduced uptake of 11C-BU99008 in the temporal lobe region reflects astrocyte dystrophy, caused by a chronic pro-inflammatory and neurotoxic amyloid-induced astrocyte phenotype resulting in reduced glycolytic capacity and impairment. secondary neuronal metabolism or cell loss.
There are obvious limits to the study of scientists. First, only a small number of subjects could be examined. A second limitation was the cross-sectional design, which scientists recognize; however, postmortem pathology has the same limitation. The authors' results are therefore best interpreted descriptively and suggesting a hypothetical model, rather than a solid and independent test.
Nonetheless, the consistency of effect directions observed in this study and previous PET 11C-DED studies provide compelling support for the proposed model, where astrocyte reactivity occurs in response to early deposition of β-amyloid plaques, aiding in the clearance of β-amyloid plaques, but where after time the astrocytes become neurotoxic, contributing to reduced tissue activity and cell death associated with cognitive impairment.
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