1. Microglial Drug Targets in AD: Opportunities and Challenges in Drug Discovery and Development
The purpose of this review article is to inform the reader of the biological indications of microglial proteins or pathways as potential targets for drug development in combating AD. The article then reviews the compatibility for AD and the challenges of pharmaceutical development for commonly identified microglial targets (CD33, KYN, P2X7, PD-1, TLRs, & TREM2). One main personal take away from the review article is that just because we have identified a pathway or a receptor does not mean we automatically have a way of targeting it for a specific treatment - the interconnectedness systems creates a difficult complexity in drug development. One bias to be aware of is that most of the lead authors have minimal research published on biology that’s not microglial cells; it was definitely in their favor to make the claim that several risk factors for AD are expressed in microglial cells. Nevertheless, this review aids in the research for my project because it lays out the biology of target differentiation for drug treatment. This topic is a large precursor to any step moving forward on AD treatment.
Citation: Biber K, et al (2019) Microglial Drug Targets in AD: Opportunities and Challenges in Drug Discovery and Development. Front. Pharmacol. 10:840. doi: 10.3389/fphar.2019.00840.
2. Phosphorylated tau interactome in the human Alzheimer's disease brain
The main goal of this research was to understand the interactive proteins surrounding the phosphorylation of tau. In doing this, the researchers found an overlap of proteins associated with the phosphorylation of tau and the formation of neurofibrillary tangles, specifically they found seventy-five proteins. The finding of this study is important to my research topic because it is able to identify the underlying proteome behind indicators of AD. In assessing the credibility of this paper, I considered that a couple of the lead authors in the study have several reviewed publications on different issues to do with AD - interactome, RNA binding proteins, therapeutic targets for amyloid sites, tau phosphorylation, etc.
Citation: Drummond E, et al. Phosphorylated tau interactome in the human Alzheimer's disease brain. Brain. 2020 Sep 1;143(9):2803-2817. doi: 10.1093/brain/awaa223.
3. Interaction between Aβ and Tau in the Pathogenesis of Alzheimer's Disease
This review article focuses on depicting the relationship between amyloid-β proteins and phosphorylated tau proteins. The first diagram pictured below describes the process between these two proteins that show reciprocal toxicity, ultimately leading to apoptosis. The second diagram from the article depicts the inflammatory cascade caused by microglia in response to Aβ or tau protein. This review is important to my research topic because it highlights the biological processes involved in apoptosis, which is pertinent to the activities of tau pathology and neurodegeneration, thus important to AD.
Citation: Zhang H, et al. Interaction between Aβ and Tau in the Pathogenesis of Alzheimer's Disease. Int J Biol Sci. 2021 May 27;17(9):2181-2192. doi: 10.7150/ijbs.57078.
This primary article describes research done using iPSC-derived cerebral organoids to identify phenotypic symptoms in patients with the APOE ε3/ε3 or ε4/ε4 genotype. Their main goal was to identify the same phenotypes in a model that is directly relevant to the human as the phenotypes previously found in mouse models; this finding would help them either confirm or deny how pertinent the mouse model really was to the human model. This paper is extremely relevant to my own research project as it goes into the process of iPSC technology relative to cerebral models. It also helps me understand the role that APOE4 plays as a genetic risk factor for AD. In evaluating the authority of the researchers, many of them have several publications on different aspects of neurodegeneration which gives them credibility on this paper.
Citation: Zhao J, et al. APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer's disease patient iPSC-derived cerebral organoids. Nat Commun. 2020 Nov 2;11(1):5540. doi: 10.1038/s41467-020-19264-0.
Alonso, A. del C, et al. Hyperphosphorylation induces self-assembly of τ into tangles of paired helical filaments/straight filaments. The National Academy of Sciences, 2001 June; 98(12). 6923-6928. doi: 10.1073pnas.121119298.
Alzheimer's Disease Facts and Figures. Alzheimer's Disease and Dementia. (n.d.). https://www.alz.org/alzheimers-dementia/facts-figures#:~:text=More%20than%206%20million%20Americans%20of%20all%20ages%20have%20Alzheimer%27s,older%20(10.7%25)%20has%20Alzheimer%27s
Cao, Y., et al. Promising candidates from drug clinical trials: Implications for clinical treatment of Alzheimer's disease in China. Front. Neurol., 15 November 2022; Sec. Dementia and Neurodegenerative Diseases, Vol. 13. https://doi.org/10.3389/fneur.2022.1034243.
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How Alzheimer's Changes the Brain. Youtube, National Institute on Aging, 23 August 2017, https://www.youtube.com/watch?v=0GXv3mHs9AU.
Huang, Y, et al. Microglia use TAM receptors to detect and engulf amyloid beta plaques. Nat Immunol. 2021 May;22(5):586-594. doi: 10.1038/s41590-021-00913-5. Epub 2021 Apr 15. PMID: 33859405; PMCID: PMC8102389.
Janda, E., et al. Microglial Phagocytosis and Its Regulation: A Therapeutic Target in Parkinson’s Disease? Front. Mol. Neurosci., 27 April 2018, Sec. Brain Disease Mechanisms, Vol. 11. https://doi.org/10.3389/fnmol.2018.00144.
Mishan, M. A., et al. Pathogenic Tau Protein Species: Promising Therapeutic Targets for Ocular Neurodegenerative Diseases. Journal of Ophthalmic & Vision Research. 2019; 14. 491-505. 10.18502/jovr.v14i4.5459.
Swanson et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimer's Research & Therapy (2021) 13:80 https://doi.org/10.1186/s13195-021-00813-8.
The 7 Stages of Alzheimer's Disease. Pennmedicine.org. (n.d.). Retrieved March 22, 2023, from https://www.pennmedicine.org/updates/blogs/neuroscience-blog/2019/november/stages-of-alzheimers.
U.S. Department of Health and Human Services. (2017, May 16). What Happens to the Brain in Alzheimer's Disease? National Institute on Aging. Retrieved March 22, 2023, from https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease#:~:text=Amyloid%20plaques,thought%20to%20be%20especially%20toxic
Xia, Y., Prokop, S. & Giasson, B.I. “Don’t Phos Over Tau”: recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer’s disease and other tauopathies. Mol Neurodegeneration 2021; 16(37). doi: 10.1186/s13024-021-00460-5.