Phytohemagglutinin: A Tool for Inducing Neuroinflammation Mediated In Vitro and In Vivo Modeling of Alzheimer's Disease Pathology

Abstract

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder and the major cause of dementia globally. One of the major barriers to curing AD is the lack of experimental models that fully recapitulate the complexity of human AD pathology. Evidence supports the notion that neuroinflammation is a key pathological contributing factor of AD. Therefore, various external stimuli are used to recapitulate the AD-like pathology, i.e., LPS, scopolamine, and aluminum chloride. Although PHA is reported for its pro-inflammatory activity, using PHA to recapitulate the AD-like pathology is relatively new. The current study was designed to evaluate the PHA potential to recapitulate the AD-like pathology in primary neuronal culture as well as in vivo AD modeling. Since LPS is widely used, in the current study, it was used to compare it with the experimental findings using PHA. Confirmation of AD-like pathology was carried out through gene and protein expression in the in vitro study, while in vivo results were verified through behavioral and histopathological assays. It was observed that PHA mimics the AD-like pathology at the cellular level by aggregating, shrinking, and disrupting synaptic plasticity of primary neuronal cells. An elevated level of BACE1 and amyloid-β and hyperphosphorylated tau protein expression, along with reduced levels of the ADAM10 gene, evidently proves that PHA induces the AD-like pathology. Disrupted cognitive and memory patterns confirm the initiation of AD pathogenesis in the in vivo study, which is further confirmed by observing the amyloid plaques stained by Congo red (CR) dye. Based on these findings, it is concluded that PHA is a potent inducer to recapitulate neuroinflammatory-mediated AD-like pathology both in vitro and in vivo.