Neuronal loss without amyloid‐β deposits in the thalamus and hippocampus in the late period after middle cerebral artery occlusion in cynomolgus monkeys

Abstract

Conflicting evidence exists regarding whether focal cerebral infarction contributes to cerebral amyloid-β (Aβ) deposition, as observed in Alzheimer's disease. In this study, we aimed to evaluate the presence of Aβ deposits in the ipsilateral thalamus and hippocampus 12 months post-stroke in non-human primates, whose brains are structurally and functionally similar to that of humans. Four young male cynomolgus monkeys were subjected to unilateral permanent middle cerebral artery occlusion (MCAO), and another four sham-operated monkeys served as controls. All monkeys underwent magnetic resonance imaging examination on post-operative day 7 to assess the location and size of the infarction. The numbers of neurons, astrocytes, microglia and the Aβ load in the non-affected thalamus and hippocampus ipsilaterally remote from infarct foci were examined immunohistochemically at sacrifice 12 months after operation. Thioflavin S and Congo Red stainings were used to identify amyloid deposits. Multiple Aβ antibodies recognizing both the N-terminal and Cterminal epitopes of Aβ peptides were used to avoid antibody cross-reactivity. Aβ levels in cerebrospinal fluid (CSF) and plasma were examined using enzyme-linked immunosorbent assay. The initial infarct was restricted to the left temporal, parietal, insular cortex and the subcortical white matter, while the thalamus and hippocampus remained intact. Of note, there were fewer neurons and more glia in the ipsilateral thalamus and hippocampus in the MCAO group at 12 months post-stroke compared to the control group (all P < 0.05). However, there was no sign of extracellular Aβ plaques in the thalamus or hippocampus. No statistically significant difference was found in CSF or plasma levels of Aβ 40 , Aβ 42 or the Aβ 40 /Aβ 42 ratio between the two groups (P > 0.05). These results suggest that significant secondary neuronal loss and reactive gliosis occur in the non-affected thalamus and hippocampus without Aβ deposits in the late period after MCAO in non-human primates.

Iron metabolism mediates microglia susceptibility in ferroptosis

“…Ferroportin can transport iron into the blood from iron storage cells and thus maintaining systemic iron homeostasis ( McKie et al, 2000 ; Zhang et al, 2018 ), and it is coupled with ceruloplasmin or amyloid precursor protein to export iron in brain cells ( Lei et al, 2021 ). Erastin was suggested to induce ferroptosis with increased iron by regulating ferroportin in human breast carcinoma cells and endometriosis ( Ouyang et al, 2020 ; Li et al, 2021 ). Knockdown of Fpn accelerated erastin-induced ferroptosis in neuroblastoma cells ( Geng et al, 2018 ).…”

Inflammatory Responses in the Secondary Thalamic Injury After Cortical Ischemic Stroke

“…However, there are contrasting views that report the lack of association between Aβ deposition and secondary thalamic injury. In cynomolgus monkeys with neuronal loss in the affected thalamus, there are no signs of Aβ deposits in the thalamus and no detectable significant changes of Aβ peptides in the cerebrospinal fluid or plasma levels after 12 months poststroke (62). A clinical study also reports no correlation between Aβ aggregates and cerebrovascular lesions of various location, severity, and age (63,64).…”

Altered excitability of motor neuron pathways after stroke: more than upper motor neuron impairments

“…And it has been demonstrated that damage to distal sites does not occur immediately after stroke, but often occurs weeks or months after stroke. In addition, pathological changes have been observed in the thalamus and hippocampus away from the infarct area 12 weeks after stroke in cynomolgus monkeys 25. Thus, the monkeys were sacrificed 12 weeks after surgery and the bilateral median nerve was removed to prepare paraffin sections for pathological analysis (online supplemental material 1).…”