Pathophysiological Role of Microglial Activation Induced by Blood-Borne Proteins in Alzheimer's Disease

Abstract

The blood-brain barrier (BBB) restricts entry of neurotoxic plasma components, blood cells, and pathogens into the brain, leading to proper neuronal functioning. BBB impairment leads to blood-borne protein infiltration such as prothrombin, thrombin, prothrombin kringle-2, fibrinogen, fibrin, and other harmful substances. Thus, microglial activation and release of pro-inflammatory mediators commence, resulting in neuronal damage and leading to impaired cognition via neuroinflammatory responses, which are important features observed in the brain of Alzheimer's disease (AD) patients. Moreover, these blood-borne proteins cluster with the amyloid beta plaque in the brain, exacerbating microglial activation, neuroinflammation, tau phosphorylation, and oxidative stress. These mechanisms work in concert and reinforce each other, contributing to the typical pathological changes in AD in the brain. Therefore, the identification of blood-borne proteins and the mechanisms involved in microglial activation and neuroinflammatory damage can be a promising therapeutic strategy for AD prevention. In this article, we review the current knowledge regarding the mechanisms of microglial activation-mediated neuroinflammation caused by the influx of blood-borne proteins into the brain via BBB disruption. Subsequently, the mechanisms of drugs that inhibit blood-borne proteins, as a potential therapeutic approach for AD, along with the limitations and potential challenges of these approaches, are also summarized.

Keywords: Alzheimer’s disease; blood-borne protein; blood–brain barrier; microglia; neurodegeneration; neuroinflammation.

Figure 1

Schematic illustration of the polarization and phenotypic transition of microglia. Microglia remain stationary in a normal state. Various stimuli can induce the resting microglia to acquire different phenotypes. In general, M1 microglia is a pro-inflammatory phenotype, while M2 microglia is an anti-inflammatory phenotype. M1 or M2 microglia can release different substances, and these two phenotypes are interchangeable under certain conditions. Figure was created using BioRender (https://www.biorender.com/ (accessed on 5 April 2023); Agreement number: RT257J0VDX).

Figure 2

The blood–brain barrier (BBB) in the healthy brain. (A) The BBB consists of a complex cellular system of a highly specialized basal membrane, a large number of pericytes, astrocytic end feet, tight junction proteins (occludin and claudin), neurons, and microglia. The cells forming the BBB communicate with cells of the brain and in the periphery. The pericytes and endothelium share a common basement membrane and connect with a variety of transmembrane junction proteins, which aid in BBB integrity maintenance. Pericytes, endothelial cells, and neurons are connected by astrocytes. The immunological responses are regulated by microglia. (B) The BBB regulates the blood-to-brain and brain-to-blood permeation of several substances, resulting in the nourishment of the CNS, its homeostatic regulation, and communication between the CNS and peripheral tissues. Figure was created using BioRender (https://www.biorender.com/ (accessed on 6 May 2023); Agreement number: WK25BZA2TM).

Figure 3

The blood-borne proteins interact with various receptors on the microglial cells to activate downstream signaling and influence various inflammatory and neurodegenerative processes in Alzheimer’s disease. Figure was created using BioRender (https://www.biorender.com/ (accessed on 5 April 2023); Agreement number: ST257J0OKO).

Figure 4

Targets of various anticoagulants in the coagulation cascade. Figure was created using BioRender (https://www.biorender.com/ (accessed on 5 April 2023); Agreement number: NB257IZC0E).