Common Mechanisms of Alzheimer's Disease and Ischemic Stroke: The Role of Protein Kinase C in the Progression of Age-Related Neurodegeneration

Abstract

Ischemic stroke and Alzheimer’s disease (AD), despite being distinct disease entities, share numerous pathophysiological mechanisms such as those mediated by inflammation, immune exhaustion, and neurovascular unit compromise. An important shared mechanistic link is acute and chronic changes in protein kinase C (PKC) activity. PKC isoforms have widespread functions important for memory, blood-brain barrier maintenance, and injury repair that change as the body ages. Disease states accelerate PKC functional modifications. Mutated forms of PKC can contribute to neurodegeneration and cognitive decline. In some cases the PKC isoforms are still functional but are not successfully translocated to appropriate locations within the cell. The deficits in proper PKC translocation worsen stroke outcome and amyloid-β toxicity. Cross talk between the innate immune system and PKC pathways contribute to the vascular status within the aging brain. Unfortunately, comorbidities such as diabetes, obesity, and hypertension disrupt normal communication between the two systems. The focus of this review is to highlight what is known about PKC function, how isoforms of PKC change with age, and what additional alterations are consequences of stroke and AD. The goal is to highlight future therapeutic targets that can be applied to both the treatment and prevention of neurologic disease. Although the pathology of ischemic stroke and AD are different, the similarity in PKC responses warrants further investigation, especially as PKC-dependent events may serve as an important connection linking age-related brain injury.

Thalassemia and risk of dementia: A nationwide population-based retrospective cohort study

“…Vascular endothelial cell injury with endovascular inflammatory processes caused by hemolytic anemia, ischemic stroke or poor tissue perfusion could lead to Alzheimer's disease or vascular dementia [24][25][26]. In addition, a profound hemostatic change with a hypercoagulable state has also been recognized in patients with β-thalassemia major, β-thalassemia intermedia, and α-thalassemia (hemoglobin H disease) [27].…”

Vascular dysfunction in the pathogenesis of Alzheimer's disease — A review of endothelium-mediated mechanisms and ensuing vicious circles

“…Alterations in this enzyme have been reported in aging and dementia [130]. In AD, the activity of PKC and its isoforms is reduced in the cortex and hippocampus [131][132][133][134], and also in cerebral microvessels [44,135].…”

The C1 domain of Vav3, a novel potential therapeutic target

“…In consequence of their central role in cellular signaling, PKC and the related classes of DAG-responsive proteins have been found to be prominently involved in cancer [7], diabetes [9], Alzheimer’s disease [10], cardiovascular disease [11] and numerous other conditions [12–14]. Complementary therapeutic strategies have targeted both the catalytic activity and the C1 regulatory domain.…”