The Potential Role of Cytokines and Growth Factors in the Pathogenesis of Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is one of the most prominent neurodegenerative diseases, which impairs cognitive function in afflicted individuals. AD results in gradual decay of neuronal function as a consequence of diverse degenerating events. Several neuroimmune players (such as cytokines and growth factors that are key players in maintaining CNS homeostasis) turn aberrant during crosstalk between the innate and adaptive immunities. This aberrance underlies neuroinflammation and drives neuronal cells toward apoptotic decline. Neuroinflammation involves microglial activation and has been shown to exacerbate AD. This review attempted to elucidate the role of cytokines, growth factors, and associated mechanisms implicated in the course of AD, especially with neuroinflammation. We also evaluated the propensities and specific mechanism(s) of cytokines and growth factors impacting neuron upon apoptotic decline and further shed light on the availability and accessibility of cytokines across the blood-brain barrier and choroid plexus in AD pathophysiology. The pathogenic and the protective roles of macrophage migration and inhibitory factors, neurotrophic factors, hematopoietic-related growth factors, TAU phosphorylation, advanced glycation end products, complement system, and glial cells in AD and neuropsychiatric pathology were also discussed. Taken together, the emerging roles of these factors in AD pathology emphasize the importance of building novel strategies for an effective therapeutic/neuropsychiatric management of AD in clinics.

Keywords: Alzheimer’s disease; blood brain barrier; brain health; chemokines; cytokines; mild cognitive impairment; neuroinflammation; neurotrophic factors; pathophysiology; therapeutics.

Figure 1

Schematic representation of MCI, linked with up-regulation of TNF-α and decrease in TGF-β characterized by upregulation of IL-1β and Aβ42 expressions. The blue arrows (↑) indicate downstream cellular events, upward green arrows (↑) indicate upregulation, downward red arrow (↓) indicates down-regulation, and plus sign (+) indicates enhanced activity.

Figure 2

Schematic diagram showing impact of LPS on elicited CCL2 activity in turn leading to aberrant hippocampal plasticity. The blue arrows (↑) indicate downstream cellular events, upward green arrow (↑) indicates upregulation, and minus sign (−) indicates decreased activity.

Figure 3

Pro-inflammatory cytokines and chemoattractant cytokines are key characteristic of neuroinflammation that can be acquired by the activation of microglia and can escalate neurodegeneration. Abnormalities in the TREM2 variant lead to defective microglial activation and decrease its phagocytic ability. The blue arrows (↑) indicate downstream cellular events, upward green arrows (↑) indicate upregulation, downward red arrows (↓) indicate down-regulation, and minus signs (−) indicate decreased activity.

Figure 4

Absence of CX3CL1 upregulates LPS response leading to increase in TNF-α expression. TNFR1 in turn regulates CPLA2 to stimulate arachidonate release. Arachidonate release can further lead to IL-1 release from macrophages. The blue arrows (↑) indicate downstream cellular events, upward green arrows (↑) indicate upregulation, and minus sign (−) indicates decreased activity.

Figure 5

Schematic representation of functional control across BBB by hematopoietic growth factors. The blue arrows (↑) indicate downstream cellular events, blue lines (T) indicate restriction, upward green arrows (↑) indicate upregulation, downward red arrows (↓) indicate down-regulation, and minus sign (−) indicates decreased activity.