Assessing the role of primary healthy microglia and gap junction blocker in hindering Alzheimer’s disease neuroinflammatory type: Early approaches for therapeutic intervention

Abstract

Alzheimer’s disease (AD) is a predominantly heterogeneous disease with a highly complex pathobiology. The presence of amyloid-beta (Aβ) depositions and the accumulation of hyperphosphorylated tau protein remain the characteristic hallmarks of AD. These hallmarks can be detected throughout the brain and other regions, including cerebrospinal fluid (CSF) and the spinal cord. Microglia cells, the brain-resident macrophage type of the brain, are implicated in maintaining healthy brain homeostasis. The localized administration of primary healthy microglia (PHM) is suggested to play a role in mitigating AD hallmark depositions and associated cognitive dysfunction. Carbenoxolone (CBX) is the most common gap junction blocker. It cannot effectively cross the blood–brain barrier (BBB) under systemic administration. Therefore, localized administration of CBX may be a recommended intervention against AD by acting as an antioxidant and anti-inflammatory agent. This study aims to determine whether the localized intracerebroventricular (ICV) administration of PHM and CBX may act as an effective therapeutic intervention for AD neuroinflammatory type. In addition, this study also aims to reveal whether detecting AD hallmarks in the spinal cord and CSF can be considered functional and effective during AD early diagnosis. Male albino rats were divided into four groups: control (group 1), lipopolysaccharide (LPS)-induced AD neuroinflammatory type (group 2), ICV injection of LPS + isolated PHM (group 3), and ICV injection of LPS + CBX (group 4). Morris water maze (MWM) was conducted to evaluate spatial working memory. The brain and spinal cord were isolated from each rat with the collection of CSF. Our findings demonstrate that the localized administration of PHM and CBX can act as promising therapeutic approaches against AD. Additionally, Aβ and tau toxic aggregates were detected in the spinal cord and the CSF of the induced AD model concomitant with the brain tissues. Overall, it is suggested that the ICV administration of PHM and CBX can restore normal brain functions and alleviate AD hallmark depositions. Detecting these depositions in the spinal cord and CSF may be considered in AD early diagnosis. As such, conducting clinical research is recommended to reveal the benefits of related therapeutic approaches compared with preclinical findings.

The emerging mechanism behind viral infections and extracellular vesicles hypotheses leading to neuroinflammation and Alzheimer's disease pathology

“…5,14 During healthy homeostatic balanced conditions, microglia cells support neuronal functions and maintain connectivity. 14,15 Additionally, the main roles of microglia cells also involve maintaining myelin homeostasis, synaptic pruning, and tissue surveillance. 5,14 Upon instant viral invasion, microglia cells were found to be heavily activated and shifted from the balanced homeostatic phase to their enlarged cell body phenotype with various retracted cell processes.…”

“…Microglia cells are the resident phagocytes macrophage type within the brain which act as the first shield against pathogenesis and inflammation 5,14 . During healthy homeostatic balanced conditions, microglia cells support neuronal functions and maintain connectivity 14,15 .…”

“…Microglia cells are the resident phagocytes macrophage type within the brain which act as the first shield against pathogenesis and inflammation 5,14 . During healthy homeostatic balanced conditions, microglia cells support neuronal functions and maintain connectivity 14,15 . Additionally, the main roles of microglia cells also involve maintaining myelin homeostasis, synaptic pruning, and tissue surveillance 5,14 .…”

“…To find out their exact roles during infection, the effects of microglia pharmaceutical depletion under viral infections were studied. Upon microglial depletion, a significant increase in the mortality rate of the central nervous system (CNS)‐infected models was reported 14 . Furthermore, viral loads within the infected CNS models were highly enhanced under conditions of microglial cell depletion.…”

“…Symptoms associated with AD and its related disorders are mainly due to hallmarks deposition including extracellular amyloid‐beta (Aβ) aggregations and intracellular tau proteins ending with severe brain damage 3 . Currently, the most known underlying AD causes and hypotheses are unregulated Aβ cascade, microgliosis, neuroinflammation, and viral infections 4,5 . In light of the recent COVID‐19 pandemic and its related neurological complications, 6,7 viral infection hypothesis‐related AD complications have gained a lot of attention where the idea that a viral infection can act as a predisposing factor for AD goes back to 8 .…”