Autophagosomes accumulation is associated with β‐amyloid deposits and secondary damage in the thalamus after focal cortical infarction in hypertensive rats

Abstract

J. Neurochem. (2012) 120, 564–573. Abstract Focal cerebral cortical infarction after distal middle cerebral artery occlusion causes β‐amyloid deposition and secondary neuronal degeneration in the ipsilateral ventroposterior nucleus of the thalamus. Several studies suggest that autophagy is an active pathway for β‐amyloid peptide generation. This study aimed to investigate the role of autophagy in thalamic β‐amyloid deposition and neuronal degeneration after cerebral cortical infarction in hypertensive rats. At 7 and 14 days after middle cerebral artery occlusion, neuronal death and β‐amyloid deposits were evident in the ipsilateral ventroposterior nucleus, and the activity of β‐site amyloid precursor protein (APP)‐cleaving enzyme 1, required for β‐amyloid peptide generation, was elevated in the thalamus. In correlation, both the number of cells showing punctate microtubule‐associated protein 1A light chain 3 fluorescence and levels of light chain 3‐II protein, an autophagosome marker, were markedly increased. Notably, most of the cells that over‐expressed β‐site APP‐cleaving enzyme 1 displayed punctate light chain 3 staining. Furthermore, the inhibition of autophagy with 3‐methyladenine significantly reduced the thalamic neuronal damage, β‐amyloid deposits, and β‐site APP‐cleaving enzyme 1 activity. These results suggest that autophagosomes accumulate within thalamic cells after cerebral cortical infarction, which is associated with thalamic β‐amyloid deposition and secondary neuronal degeneration via elevation of β‐site APP‐cleaving enzyme 1 level.

Secondary Neurodegeneration in Remote Regions After Focal Cerebral Infarction

“…45 We investigated the role of macroautophagy in the secondary thalamic degeneration after cerebral cortical infarction in rats and found that macroautophagy was activated in the ipsilateral thalamic cells. 46,47 Furthermore, macroautophagic inhibitor and Beclin-1 knockdown significantly reduced the macroautophagic activation and neuronal loss, suggesting macroautophagy may act in cell death in secondary thalamic degeneration. 46,47 To further understand the role of macroautophagy in secondary degeneration, it is necessary to investigate exactly how macroautophagy contributes to cell death and its relationship with other cell death pathways.…”

“…Inhibition of macroautophagy prevented the A␤ accumulation and, conversely, reduction of A␤ suppressed macroautophagy activation. 46,47 Future studies are needed to elucidate the underlying mechanisms.…”

Physical Exercise Promotes Recovery of Neurological Function after Ischemic Stroke in Rats

“…The area immediately outside of this zone is referred to as the “peri-infarct”, in which most neurons do not display the histological signs of irreversible damage [34]. The volumes of the ipsilateral and the contra-lateral hemisphere were counted as described previously [3,35,36] and the relative infarct volume was described as a percentage of the contra-lateral hemisphere. All the mNSS, infarct size calculation and immunostaining quantitation were performed blinded, which were reviewed and analyzed separately by two independent researchers.…”

Autophagy and Neuronal Cell Death in Neurological Disorders

“…Similar observations on this injury model have been made using 3MA to assess the involvement of autophagy in neuronal death. (Wen et al 2008;Puyal et al 2009;Piras et al 2011;Wang et al 2011;Xin et al 2011;Zhang 2012). Beneficial effects of autophagic inhibition have also been seen in several models of chronic neurodegenerative diseases.…”