The Role of Autophagy in the Correlation Between Neuron Damage and Cognitive Impairment in Rat Chronic Cerebral Hypoperfusion

Abstract

Pathological changes and cognitive impairment caused by chronic cerebral hypoperfusion (CCH) have been previously reported. However, how these changes progress remains unclear. Additionally, there are few studies regarding the mechanism underlying the involvement of autophagy in these processes. Two-step bilateral common carotid artery occlusion (BCCAO) was performed to replicate CCH in Sprague Dawley rats. The animals were divided into seven groups, including a sham group and 2-, 4-, 8-, 12-, 16-, and 20-week BCCAO groups (n = 7 per group). Five additional rats were used to monitor cerebral blood fluid (CBF) changes via laser speckle contrast imaging (LSCI). We tested for cognitive changes and pathological changes, including neuronal injury, white matter lesions, and β-Amyloid (Aβ) deposition, via acknowledged methods. Autophagy was analyzed via western blotting and immunohistochemistry. Cognitive impairment appeared beginning at 8 weeks after BCCAO despite improvement in CBF. Neuronal damage began at 8 weeks in the hippocampal CA1 region and at 4 weeks in the cortex. White matter injury was detected in all BCCAO groups. Intracellular Aβ accumulation occurred earlier than extracellular plaque formation. The levels of autophagy-related proteins (Beclin-1, light chain 3B, and P62) increased beginning at 2 weeks in the cortex and at 4 weeks in the hippocampus and remained elevated throughout the remainder of the study period. Despite recovery of CBF, autophagy dysfunction occurred early after CCH and played an important role in neuronal deterioration, cognitive decline, and intracellular Aβ aggregation.

TREM-2-p38 MAPK signaling regulates neuroinflammation during chronic cerebral hypoperfusion combined with diabetes mellitus

“…Subsequently, these rats exhibit clinically relevant characteristics of T2DM were further subjected to BCCAO surgery, which has been widely used to constitute the pathological condition of CCH. Our study found that CBF decreased significantly by more than 70% immediately after BCCAO, comparable with that observed in clinical patients [18]. Additionally, we found that compared with the CCH group, CBF decrease was more pronounced in the DM-CCH group, but without statistical difference.…”

“…Neuronal degeneration and memory deficits caused by CCH have been extensively reported [7,30]. Consistently, we have previously found that neuronal injury and cognitive impairment are prominent at 8 weeks following BCCAO [18]. Similarly, studies also found that STZ-induced DM could aggravate neuronal apoptosis and cognitive dysfunction in rodents [31].…”

“…Rats were recognized as diabetic rats when glucose levels reached 16.7 mM after 1 week of STZ injection. Two weeks after STZ injection, animals were subjected to either sham treatment or two-step BCCAO according to the procedure previously described [18]. Briefly, rats were anesthetized intraperitoneally with chloral hydrate (350 mg/kg).…”

Dl‑3n‑butylphthalide improves spatial learning and memory in rats with vascular dementia by reducing autophagy via regulation of the mTOR signaling pathway

“…Autophagy, which is an adaptive reaction of cells to stress produced by alterations in the internal and external environments, is a dynamic catabolic process involved in multiple cellular processes (21). However, excessive autophagy may trigger cell death and contribute to ischemia-induced neuronal damage (22,23). Inhibition of autophagy has thus demonstrated beneficial effects in modulating neurological deficits following cerebral ischemia (24,25).…”

Deterioration of cognitive function after transient cerebral ischemia with amyloid-β infusion—possible amelioration of cognitive function by AT2 receptor activation

“…Neuronal pyknosis detected by HE staining has widely been used as a marker for neuronal degeneration after ischemic brain damage recently [45]. To evaluate neuronal degeneration, we examined neuronal pyknosis with HE staining and analyzed mRNA expression of apoptosis genes.…”