Malina Maharana

Introduction. Alzheimer’s Disease (AD) is a neurodegenerative disease characterized by progressive cognitive and neurobehavioral impairment.¹ AD is marked by aggregates of Aβ plaques and tau tangles, which cause neuroinflammation.² This leads to activation of reactive astrocyte A1, which is neurotoxic.^3,4 Amyloid plaques are formed by the accumulation of Aβ monomers, which activate through neuroinflammation and astrocytosis in a positive feedback loop.⁵ Harmful effects of reactive astrocytes and Aβ accumulation may be mediated by polyphenolic nutraceuticals. Methods. To investigate whether microglia induced A1 astrocytes, Csf1r-/- knockout mice without microglia analyzed through quantitative (q)PCR. To test neurotoxicity, A1 astrocytes were cultured with purified retinal ganglion cells (RCGs) and measured for viability.³ Astrocytes were seeded, fixed, dried, and stained with various antibodies (C3) and processed in ELISA.⁴ An MTT Assay was performed to determine phloroglucinol’s effect on levels of intracellular ROS.⁵ To analyze for OxyR-mediated autophagic flux activation, autophagic activities were measured through immunostaining and immunoblotting assays.⁶ Blood samples of patients were collected at baseline and post curcumin intervention and analyzed using ELISA kits for GSK-3β and IAPP.⁷ Results. C3 serves a central role in the complement system and is highly induced through A1 astrocytes over A2 astrocytes, confirmed by ELISA.⁵ Once treated with A1 reactive astrocytes, both RGCs and differentiated astrocytes are killed in an inflammatory matter.³ MFG-E8 was successful in inducing apoptotic phagocytosis and release of anti-inflammatory factors against C3 expressing A1 astrocytes in a dose-dependent manner.⁴ Phloroglucinol had protective activity in primary cultured astrocytes by ROS induced by Aβ1-42, which reduced the possibility of activating neurotoxic A1 astrocytes.⁵ Oxyresveratrol (OxyR) was found to inhibit Aβ production by inhibiting β-secretase. OxyR directly affects amyloid precursor protein modulation through the autophagy pathway.⁶ Curcumin supplementation significantly lowered GSK-3β and IAPP (markers of insulin resistance in the pancreas and amyloid burden in the brain).⁷ Conclusion. Amyloid precursor proteins aggregate and produce reactive A1 astrocytes, which contribute to neurodegeneration and disease progression. These A1 astrocytes lose the ability to phagocytose debris, promote neuronal and synapse survival, and upregulate classical complement cascade genes, which is neurotoxic.^3,4 Targeting neuroinflammation caused by hallmarks of AD with polyphenolic neutraceuticals is sustainable, as AD is largely prevalent in older populations. Polyphenolic neutraceuticals may be the answer we were searching for in treating AD.^3,4,5,6 It’s currently poorly understood if neuroinflammation is caused by or leads to reactive astrocytosis and Aβ production. Evidence points to both, but further research must be conducted.^3,5

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5. Yang EJ, Kim H, Kim HS, Chang MJ. Phloroglucinol attenuates oligomeric amyloid beta peptide1-42-induced astrocytic activation by reducing oxidative stress. J Pharmacol Sci. 2021;145(4):308-312. doi:10.1016/j.jphs.2021.01.008
6. Rahman MA, Cho Y, Nam G, Rhim H. Antioxidant Compound, Oxyresveratrol, Inhibits APP Production through the AMPK/ULK1/mTOR-Mediated Autophagy Pathway in Mouse Cortical Astrocytes. Antioxidants (Basel). 2021;10(3):408. Published 2021 Mar 8. doi:10.3390/antiox10030408
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