An investigation into the combined effects of β-amyloid toxicity and cerebral ischemia on the pathological expression of gangliosides.

Identifying mechanisms underlying the synergistic pathological interaction between stroke and Alzheimer’s disease (AD) can effectively guide future therapeutic strategies for these highly co-morbid conditions. Aberrant ganglioside expression marked by the pathological accumulation of ganglioside GM3 is common to stroke and AD, yet it is unclear whether GM3 is synergistically enhanced in a comorbid model, or if GM3 is a viable therapeutic target. Adult male Wistar rats received a unilateral ischemic striatal infarct via endothelin-1 (ET-1) injection alone or in combination with bilateral intracerebroventricular injection of the β-Amyloid 25-35 peptide (Aβ) to induce generalized Aβ toxicity (Aβ/ET-1). Animals were sacrificed after 3 or 21 days and assessed via immunohistochemistry for neuroinflammation, neurodegeneration, and ganglioside expression. Other animals were also treated with chloroquine (CQ) systemically for seven days beginning 3 days before surgery as a novel therapeutic approach to prevent the accumulation of GM3 by inhibiting degradation of complex gangliosides. Our results showed that Aβ/ET-1 synergistically enhanced GM3 accumulation with concomitant reductions in complex gangliosides and neuronal survival at 21 days. CQ reduced inflammation and GM3 accumulation at 21 days, and improved neuronal survival. These findings suggest GM3 accumulation is a point of synergism between stroke and Aβ toxicity, and CQ may be a viable therapeutic approach for stroke