Objective
Fragile X‐associated tremor/ataxia syndrome (FXTAS) is a late‐onset progressive genetic neurodegenerative disorder that occurs in FMR1 premutation carriers. The temporal, spatial, and ...cell‐type specific patterns of neurodegeneration in the FXTAS brain remain incompletely characterized. Intranuclear inclusion bodies are the neuropathological hallmark of FXTAS, which are largest and occur most frequently in astrocytes, glial cells that maintain brain homeostasis. Here, we characterized neuropathological alterations in astrocytes in multiple regions of the FXTAS brain.
Methods
Striatal and cerebellar sections from FXTAS cases (n = 12) and controls (n = 12) were stained for the astrocyte markers glial fibrillary acidic protein (GFAP) and aldehyde dehydrogenase 1L1 (ALDH1L1) using immunohistochemistry. Reactive astrogliosis severity, the prevalence of GFAP+ fragments, and astrocyte density were scored. Double label immunofluorescence was utilized to detect co‐localization of GFAP and cleaved caspase‐3.
Results
FXTAS cases showed widespread reactive gliosis in both grey and white matter. GFAP staining also revealed remarkably severe astrocyte pathology in FXTAS white matter – characterized by a significant and visible reduction in astrocyte density (−38.7% in striatum and − 32.2% in cerebellum) and the widespread presence of GFAP+ fragments reminiscent of apoptotic bodies. White matter specific reductions in astrocyte density were confirmed with ALDH1L1 staining. GFAP+ astrocytes and fragments in white matter were positive for cleaved caspase‐3, suggesting that apoptosis‐mediated degeneration is responsible for reduced astrocyte counts.
Interpretation
We have established that FXTAS neuropathology includes robust degeneration of astrocytes, which is specific to white matter. Because astrocytes are essential for maintaining homeostasis within the central nervous system, a loss of astrocytes likely further exacerbates neuropathological progression of other cell types in the FXTAS brain. ANN NEUROL 2024;95:558–575
Autism spectrum disorder is a neurodevelopmental condition characterized by impaired social communication and repetitive behaviors. Changes in the number of specific cell types in the cerebral cortex ...could produce a dramatic alteration in the regulation of cortical circuits, and thus an alteration of behavior. We investigated whether there are layer-specific changes in the number of neurons, astrocytes, and oligodendrocytes in the prefrontal cortex in postmortem human brains from autism spectrum disorder subjects. We quantified the number of specific cell types in the prefrontal cortex (Brodmann areas 9, 46, and 47) of 10 cases with autism spectrum disorder and 10 age-matched control cases. We found that the number of neurons was increased and the number of astrocytes was decreased in layer II of all three prefrontal areas. Area BA47 was most widely affected presenting with an increased number of neurons and a decreased number of astrocytes in layer II and deeper layers of the cortex. Among other possibilities, the alterations in neuron and glial cell number we report here are consistent with a failure of radial glial cells to shift daughter cell production from neurons to astrocytes during prenatal cortical development in autism spectrum disorder. The data provided here are key anatomical findings that shed light on autism spectrum disorder pathogenesis.
Lay abstract
The cerebral cortex affected with autism spectrum disorder presents changes in the number of neurons and glia cells, possibly leading to a dysregulation of brain circuits and affecting behavior. However, little is known about cell number alteration in specific layers of the cortex in autism spectrum disorder. We found an increase in the number of neurons and a decrease in the number of astrocytes in specific layers of the prefrontal cortex in postmortem human brains from autism spectrum disorder cases. We hypothesize that this may be due to a failure in neural stem cells to shift differentiation from neurons to glial cells during prenatal brain development. These data provide key anatomical findings that contribute to the bases of autism spectrum disorder pathogenesis.
Varicose projection astrocytes (VP‐As) are found in the cerebral cortex and have been described to be specific to humans and chimpanzees. To further examine the phylogenetic distribution of this cell ...type, we analyzed cortical tissue from several primates ranging from primitive primates to primates evolutionary closer to human such as apes. We specifically analyzed tissue from four strepsirrhine species, one tarsier, six species of platyrrhine monkeys, ten species of cercopithecoid monkeys, two hylobatid ape species, four to six cases each of chimpanzee, bonobo, gorilla, and orangutan, and thirteen human. We found that VP‐As were present only in human and other apes (hominoids) and were absent in all other species. We showed that VP‐As are localized to layer VI and the superficial white matter of the cortex. The presence of VP‐As co‐occured with interlaminar astrocytes that also had varicosities in their processes. Due to their location, their long tangential processes, and their irregular presence within species, we propose that VP‐As are astrocytes that develop varicosities under specific conditions and that are not a distinct astrocyte type.
Main Points
Varicose projection astrocytes (VPAs) are present in hominoids (apes) but not in other primates and are concomitantly found with interlaminar astrocytes bearing varicosities.
VP‐As may not be a distinct astrocyte type, but astrocytes morphologically modified under specific brain conditions.
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