Abstract
In this work, we evaluated the effects of alpha linoleic acid (ALA), an omega-3 polyunsaturated fatty acid, on amyloid-beta-induced glial-cell-mediated neuroinflammation, amyloidogenesis, and cognitive dysfunction in mice. After an infusion of Aβ1–42 (Aβ1–42, 5 μL/5 min/mouse, intracerebroventricular injection (i.c.v), and respective treatments of ALA (60 mg/kg per oral for six weeks), neuroinflammation, apoptotic markers, and synaptic markers were evaluated by Western blot and immunofluorescence analyses. According to our findings, the infusion of Aβ1–42 activated Toll-like receptor 4 (TLR4), glial fibrillary acidic protein (GFAP), and ionized calcium adaptor molecule 1 (Iba-1) in the frontal cortices and hippocampi of the Aβ1–42-injected mice to a greater extent than the Aβ1–42 + ALA-cotreated mice. Similarly, there was an elevated expression of phospho-c-Jun-N-terminal kinase (p-JNK), phospho-nuclear factor-kB p65 (p-NF-kB p65 (Ser536)), and tissue necrosis factor (TNF) in the Aβ1–42 infused mouse brains; interestingly, these markers were significantly reduced in the Aβ + ALA-cotreated group. The elevated expression of pro-apoptotic markers was observed during apoptotic cell death in the Aβ1–42-treated mouse brains, whereas these markers were markedly reduced in the Aβ + ALA-cotreated group. Moreover, Aβ1–42 infusion significantly increased amyloidogenesis, as assessed by the enhanced expression of the amyloid precursor proteins (APP) beta-amyloid cleaving enzyme-1 (BACE-1) and amyloid-beta (Aβ1–42) in the mouse brains, whereas these proteins were markedly reduced in the Aβ + ALA-cotreated group. We also checked the effects of ALA against Aβ-triggered synaptic dysfunction and memory dysfunction, showing that ALA significantly improved memory and synaptic functions in Aβ-treated mouse brains. These results indicated that ALA could be an applicable intervention in neuroinflammation, apoptotic cell loss, amyloidogenesis, and memory dysfunction via the inhibition of TLR4 and its downstream targets in Aβ + ALA-cotreated mouse brains.
Highlights
Alzheimer’s disease (AD) is a slowly progressive, chronic neurological disease characterized by the loss of memory and cognition [1,2]
We evaluated Toll-like receptor-4 (TLR4) and glial fibrillary acid protein (GFAP) expression levels in the brains of the treated groups through immunofluorescence analysis, as these are considered to be the crucial mediators of neurodegenerative conditions [17]
The elevated expressions of these markers were significantly reduced in the amyloid β (Aβ) + Alpha linoleic acid (ALA)-cotreated mouse brains
Summary
Alzheimer’s disease (AD) is a slowly progressive, chronic neurological disease characterized by the loss of memory and cognition [1,2]. Microglial cells are the resident phagocytic cells of the central nervous system (CNS), and their phagocytic capacity can be modulated to improve the clearance of Aβ deposition This indicates that inhibiting the microglial phenotype, thereby switching it from the pathogenic state to the normal cognitive phenotype, or activating microglia could comprise a promising and effective therapeutic approach for AD-like neurodegenerative conditions [9]. Therfore, adequate regulation of the immune response within the CNS is critical, because most of the brain diseases are related to chronic inflammatory conditions and accompanied by microglia activation that tracks inappropriate T cell instigation and polarization. Chronic neuroinflammation accelerates neurodegeneration and contributes to the pathogenesis of Parkinson’s, Alzheimer’s disease, Huntington’s disease, multiple sclerosis, and other cognitive and memory dysfunctions [12,13]. The release of brain inflammatory cytokines may be facilitated by many factors, including pattern recognition receptors (PRRs), and Toll-like receptor-4 (TLR4)
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