Amyloid Burden, Neuroinflammation, and Links to Cognitive Decline After Ischemic Stroke

One in 5 patients with stroke will end up demented shortly after a stroke, half with prior cognitive impairment and half without. After recurrent stroke, more than a third will become demented.1 The mechanisms remain unclear beyond the fact that neurodegenerative and vascular mechanisms contribute to the cognitive decline.2 In this review, we explore experimental and clinical evidence of interaction between ischemia, amyloid deposition, and neuroinflammation and identify new potential therapeutic targets.Clinical data clearly indicate that the coexistence of stroke and Alzheimer disease (AD) leads to exacerbated dementia,3 and experimental studies with animals have addressed the relationship between stroke and AD.4–9 Although human studies have also indicated that soluble parenchymal amyloid precursor protein and β-amyloid 1 to 42 (Aβ1–42) accumulate in patients with multi-infarct dementia,10,11 there are animal studies examining neurodegenerative mechanisms and cognitive impairment in global and focal experimental ischemia. Changes in neurotransmitter systems, trophic factors, and cell signaling and neuroinflammatory mechanisms have been well documented.12 Experimental animal models of cognitive impairment have demonstrated the presence of amyloid precursor protein in the area of ischemic damage.13 Studies in mice overexpressing mutated presenilin 1 or presenilin-knockout mice suggest that presenilin 1 mutations lead to enhanced neurodegeneration after focal ischemia or excitotoxicity.9,14 This may suggest that mutations leading to higher levels of Aβ may increase the sensitivity to ischemia. In another study, mice overexpressing amyloid precursor protein with middle cerebral artery occlusion were shown to have enlarged infarcts and a stronger reduction of blood flow after the arterial occlusion.15 These experiments, however, also showed that the vasodilatory effect of the endothelium-dependent vasodilator acetylcholine was significantly reduced in transgenic mice, possibly suggesting that Aβ-induced disturbance in endothelium-dependent vascular reactivity may contribute to the higher ischemia …