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

Abstract

O ne 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. Evidence From Experimental StudiesClinical 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][5][6][7][8][9] Although human studies have also indicated that soluble parenchymal amyloid precursor protein and β-amyloid 1 to 42 (Aβ 1-42 ) 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 presenilinknockout 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 sensitivity. Our research group has conducted several studies directly examining the pathological, neuroinflammatory, and behavioral relationship of stroke and AD in rat and mouse models. [4][5][6][7] In particular, these studies have focused on the potential synergism that would account for the clinical findings. A consequence of a chronic neuroinflammatory response is perturbation of the cerebrovascular system. Likewise, a perturbation of the cerebrovascular system will influence the degree of neuroinflammation after injury. A considerable body of evidence has demonstrated that AD is directly related to and has profound pathological changes in the cerebral microvasculature.16 Specific attention has recently focused on changes within brain endothelial cells in AD and in response to exposure to Aβ. 16 It has been hypothesized that during the onset of AD the breakdow...

Clasmatodendrosis and β‐amyloidosis in aging hippocampus

“…Moreover, it has been demonstrated that the ischemic milieu triggers Ab deposition in the CNS (47,48). Our data report that Ab aggregates frequently absorb GFAP molecules, suggesting that clasmatodendrosis affects Ab deposition on neurons through the interaction between APJ fragments and Ab fibrils.…”

Protective effects of primary neural stem cell treatment in ischemic stroke models

“…Cytosolic cytochrome c release and caspase activation have been observed during ischemia-induced apoptosis (31) and NSCs are able to attenuate caspase-3 activation and impairment in OGD-treated BMECs. It has been demonstrated in vivo that NSCs affect the PI3K/Akt/GSK3β pathway, which regulates cell proliferation, survival and migration (14,32,33).…”

Cortical Selective Neuronal Loss, Impaired Behavior, and Normal Magnetic Resonance Imaging in a New Rat Model of True Transient Ischemic Attacks

“…27 Accordingly, TIAs are known to be associated with an increased long-term risk of cognitive decline and dementia. 3,4 Independent from or in addition to this classic diminished reserve mechanism, neuronal death might also directly trigger aβ deposition and facilitate Alzheimer pathology, 40,41 an effect possibly enhanced in SHRs given their naturally occurring accelerated brain aging. Thus, SNL and MA might represent therapeutic targets in patients with TIAs.…”