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.

Keywords: Alzheimer's disease; blood-brain barrier; immune exhaustion; innate immunity; ischemic stroke; protein kinase C.

Fig. 1

Following stroke, PKCδ and PKCζ become dysfunctional and are increased. The result is an increase in BBB disruption and worse ischemic infarct. If PKCε is targeted pharmacologically in order to enhance translocation to the membrane, the BBB is maintained and ischemic infarct is reduced.

Fig. 2

Neuronal injury causes dysregulation of PKC β, ζ, and α as well as an increase in PKCδ. These changes contribute to the development and progression of Aβ pathology and NFTs. Targeting PKCε with the pharmacologic agent Bryostatin may prove beneficial in protecting the brain against harmful PKC changes. By increasing PKCε, the progression of NFTs and Aβ pathology will be slowed.

Fig. 3

Glutamate activation of NMDA and AMPA receptors causes an increase in intracellular calcium. The calcium surge triggers an increase in PKCζ that subsequently leads to superoxide formation. PKC activation also contributes to the formation of nitric oxide synthase (NOS) and associated cell death. An increase in PKCε can mitigate the detrimental effects of oxidative stress and prevent conformational changes at the membrane.