Efficacy of Piper Longum Extract in a Streptozotocin-Induced Mouse Model of Sporadic Alzheimer’s Disease Combined with Chronic Restraint Through Lipocalin-2-Associated Neuroinflammatory Mechanism

Abstract Background Alzheimer’s disease (AD) is a neurodegenerative disease that is often accompanied by neuropsychiatric problems, including depression. Lipocalin-2(LCN2), a proinflammatory mediator, exacerbates the symptoms of depression and memory impairment through neuroinflammation. This study investigated the potential of Piper Longum extract(PLE), a traditional Indian medicinal plant, in the treatment of AD and comorbid depression. Methods In this study, we investigated memory impairment and depression-like behaviors through behavioral experiments such as the Y-maze test, Morris water maze test, open field test (OFT), forced swim test (FST), and tail suspension test (TST). We used Western blot, RT-PCR analysis, and immunofluorescence to identify changes in AD-related markers, such as amyloid beta (Aβ) protein, tau phosphorylation, tumor necrosis factor-alpha (TNF-α), and LCN2-related astrocytes, in the brain of Streptozotocin/Chronic Restrain Stress (STZ/Res) mice treated with PLE. Results The PLE group showed significant improvements in the Morris water maze, Y-maze, FST, and TST. Aβ protein, hyperphosphorylation of tau, TNF-α level decreased when treated PLE compared to Donepezil(DPZ). LCN2 merged with GFAP and colocalization was significantly decreased in the PLE-treated group. Conclusion Our findings suggest that Piper longum is a potential natural treatment for AD and depressive comorbidities caused by LCN2-mediated neuroinflammation. Graphical Abstract