This presentation gives an outline of the research articles presented in a review paper about a neurodegenerative disease called Alzheimer's disease and the experimental use of therapeutic stem cells. The paper discusses different types of stem cells and how they have been used on the mouse model for Alzheimer's disease.

1. Neurodegeneration and Neuro-Regeneration—
Alzheimer’s Disease and Stem Cell Therapy
V. Vasic, K. Barth, & M. H. H. Schmidt, International
Journal of Molecular Sciences 2019, 20(17), 4272
Andrew Roman
Seminar 7124
Dr. Qin Feng
April 11th, 2022
Figure 1. Different stem cell types are used to develop
various treatments for Alzheimer’s disease (Vasic et al.,
2019)

2. Key Points
• Neurodegeneration leads to dementia
• Multiple diseases cause dementia
• Brain self-repairs
• Therapeutic stimulation of adult neurogenesis
• Stem cell therapy
(Vasic et al., 2019)

3. Alzheimer’s disease
• Short-term memory loss
• Reduction in brain volume
• Daily life impaired
Figure 2. Comparison of normal brain with Alzheimer’s disease
patient (Mattson, 2004).
(Vasic et al., 2019)

4. Alzheimer’s Disease Continued
• Death of neurons
• Loss of synapses
• Amyloid-β accumulation
• Neurofibrillary tangles of tau protein
(Vasic et al., 2019)

5. Cell Types Involved with Alzheimer’s Disease
• Microglia
• Astrocytes
• Oligodendrocytes
• NG2-Glia
• Neurons
(Vasic et al., 2019)

6. Microglia
• Resident macrophages
• Function impaired in AD (Katsumoto et al., 2018)
• Activation of inflammatory pathways (Wyss-Coray et al., 2011)
• Circulating blood and mesenchyme
• Continuously survey the microenvironment
• Remove detritus
• Synaptic remodeling and plasticity
(Vasic et al., 2019)

7. Figure 3. Study showing activities of resting microglia
(Nimmerjahn et al., 2005).

8. • Impaired Aβ homeostasis alters
morphology
• Production of inflammatory
cytokines
• TREM2 activation and
microgliosis through APOE4
• ABCA7 regulation of lipid
homeostasis and phagocytosis
• P2X7 receptor overactivation
mediated by extracellular ATP
Microglia Continued
Figure 4. Different forms of Aβ and how they affect microglia
(Heppner et al., 2015).
(Vasic et al., 2019)

9. Figure 5. Colocalization in the Phagocytic Cup (Jehle et al., 2006)

10. Astrocytes in Alzheimer’s Disease
• Multiple interactions with neurons
• Synaptic plasticity
• Chemotactic response to Aβ
• Bind, take up, and degrade Aβ
• Secrete enzymes for extracellular
degradation of Aβ
Figure 6. Astrocytes remove neurotransmitters and other
substances from synaptic terminals (Fields et al., 2013)
(Vasic et al., 2019)

11. Astrocytes in Alzheimer’s Disease Continued
• Aggregation of Aβ alters receptor
expression
• Increased Ca2+ uptake
• Decreased glutamate uptake
• Inflammatory cytokines trigger Aβ
production (Blasko et al., 2000)
Figure 7. Distribution of Aβ in neurons and
astrocytes (Nagele et al., 2003)
(Vasic et al., 2019)

12. Oligodendrocytes in Alzheimer’s Disease
• Myelin deteriorates
• Axons are destroyed
• No reduction in myelin
• Aβ is cytotoxic
(Vasic et al., 2019)

13. NG2-glia
• Newly discovered cell
type
• Differentiation is inhibited
by Aβ
Figure 8. Developmental stages of NG2-glia (Nishiyama et al., 2009)
(Vasic et al., 2019)

14. Neurons
• Hyperphosphorylated tau protein forming intracellular neurofibrillary
tangles
• Phosphorylation normally allows interaction with microtubules
transporting mitochondria
• Energy dysfunction, reactive oxygen and nitrogen species
(Vasic et al., 2019)

15. Organelles and Related Processes
• Mitochondria
• Autophagy
• Endocytic processes
(Vasic et al., 2019)

16. Mitochondria
• Fission and fusion
• Distribution of mitochondria
• Neuroprotective effects
Figure 9. Loss of functional mitochondria promotes oxidative stress
(Moreira et al., 2010)
(Vasic et al., 2019)

17. Autophagy
• Pathway for degradation of cellular components
• Mitophagy
• Essential housekeeping process
• Autophagy gene mutation and AD
• Autophagy is neuroprotective and prevents protein accumulation
(Menzies et al., 2015)
(Vasic et al., 2019)

18. Endocytic Processes
• Clathrin-mediated endocytosis
• Clathrin-independent endocytic pathways
• Flotillin-1 and -2 are associated with membrane lipid-rafts
• Caveolae-1, -2, -3 in ordered lipid raft domains
• APP and Aβ toxicity
• Endosomes increased in AD
• Cav-1 downregulation
(Vasic et al., 2019)

19. Stem Cell Therapy
• Endogenous regeneration
• Engrafted regeneration
• ESCs
• NSCs
• iPSCs
• MSCs
• Translation
(Vasic et al., 2019)

20. Endogenous Regeneration
• Neurogenesis in adult hippocampus directs spatial navigation
(Ekstrom et al., 2003)
• AD affects hippocampal neurons
• 700 new neurons per day
• Induced neurogenesis in animals
• Chemicals and growth factors ex. erythropoietin, BDNF
• Exercise and CA1 region
(Vasic et al., 2019)

21. Figure 10. Exercise decreases loss of neurons in transgenic mouse model
for Alzheimer’s disease (Hüttenrauch et al., 2016)

22. Engrafted Regeneration
• Sources of stem cells for treatment vary
• Embryonic stem cells
• Neural stem cells
• Induced pluripotent stem cells
• Mesenchymal stem cells
• Treatment strategies vary
Figure 1. Different stem cell types are used to develop
various treatments for Alzheimer’s disease (Vasic et al.,
2019)
(Vasic et al., 2019)

23. Embryonic Stem Cells
• Pluripotent
• Unlimited self-renewal ability
• Derived from blastocyst
• Regulation of donated embryos
• Pre-differentiated into basal forebrain cholinergic neurons & medial
ganglionic eminence-like progenitor cells
(Vasic et al., 2019)

24. Figure 11. Characterization of neurons derived from stem cells (Moghadam et al., 2009)

25. Neural Stem Cells
• Multipotent, self-renewing producing neurons, oligodendrocytes, or
astrocytes
• Improving survival outcome
• Grafting improved mouse models
• Genes or drugs added
• Glia and TLR4 activation associated with neuroinflammation
(Vasic et al., 2019)

26. Induced Pluripotent Stem Cells
• Production of autologous cells for transplantation
• Immune rejection
• Patient derived skin fibroblasts showed ApoE4 pathogenic
• Transplanted glial cells improved cognitive function
• Neuronal precursor cells developed into cholinergic neurons
• Parkinson’s and stroke models
(Vasic et al., 2019)

27. Figure 12. Characterization of grafted hiPS neurons in mouse hippocampus
(Fujiwara et al., 2013)

28. Mesenchymal Stem Cells
• Present in bone marrow, umbilical cord, and adipose tissue
• Low rate of neuronal differentiation
• Intravenous application crosses blood brain barrier
• Results like other SC therapies
• Improved neuroprotection with downregulation of inflammation
• Genetic alterations for supplemental extracellular vesicles
• Overexpression of cytokines
(Vasic et al., 2019)

29. Translational Research
• Ongoing clinical trials
• Transplanted cells stimulate endogenous mechanisms
• MSCs ease of use
• Phase I trials of hUBC-MSCs showed no improvement
• Transduced autologous fibroblasts improved cognitive decline
• Results posted on ClinicalTrials.gov
(Vasic et al., 2019)

30. Conclusion
• Understanding of AD limited
• New data for treatments
• Translation from rodent model
problematic
• Multiple factors affect clinical
trial
• Evaluation of transplanted cells
• Diagnostic tools for early
detection
• Combination of methods for
treatments
Figure 13. Table summarizing types of stem cells (Vasic et al., 2019)
(Vasic et al., 2019)

31. Works Cited
Blasko, I., Veerhuis, R., Stampfer-Kountchev, M., Saurwein-Teissl, M., Eikelenboom, P., & Grubeck-Loebenstein, B. (2000). Costimulatory effects of interferon-γ and interleukin-1β or tumor necrosis factor α on the synthesis of Aβ1-40 and Aβ1-42 by human
astrocytes. Neurobiology of Disease, 7, 682-689. https://doi.org/10.1006/nbdi.2000.0321
Ekstrom, A. D., Kahana, M. J., Caplan, J. B., Fields, T. A., Isham, E. A., Newman, E. L., & Fried, I. (2003). Cellular networks underlying human spatial navigation. Nature, 425, 184-188. https://doi.org/10.1038/nature01964
Fields, R. D., Araque, A., Johansen-Berg, H., Lim, S.-S., Lynch, G., Nave, K.-A., Nedergaard, M., Perez, R., Sejnowski, T., & Wake, H. (2013). Glial biology in learning and cognition. The Neuroscientist, 20, 426-431.
https://doi.org/10.1177/1073858413504465
Fukiwara, N., Shimizu, J., Takai, K., Arimitsu, N., Saito, A., Kono, T., Umehara, T., Ueda, Y., Wakisaka, S., Suzuki, T., & Suzuki, N. (2013) Restoration of spatial memory dysfunction of human APP transgenic mice by transplantation of neuronal precursors
derived from human iPS cell, Neuroscience Letters, 557, 129-134. https://doi.org/10.1016/j.neulet.2013.10.043
Heppner, F. L., Ransohoff, R. M., & Becher, B. (2015). Immune attack: the role of inflammation in Alzheimer’s disease. Nature Reviews Neuroscience, 16, 358-372. https://doi.org/10.1038/nrn3880
Hüttenrauch, M., Brauß, A., Kurdakova, A., Borgers, H., Klinker, F., Liebetanz, D., Salinas-Riester, G., Wiltfang, J., Klafki, H. W., & Wirths, O. (2016). Physical activity delays hippocampal neurodegeneration and rescues memory deficits in an Alzheimer
disease mouse model. Translational Psychiatry, 6, e800. https://doi.org/10.1038/tp.2016.65
Jehle, A. W., Gardai, S. J., Li, S., Linsel-Nitschke, P., Morimoto, K., Janssen, W. J., Vandivier, R. W., Wang, N., Greenberg, S., Dale, B. M., Qin, C., Henson, P. M., & Tall, A. R. (2006). ATP-binding cassette transporter A7 enhances phagocytosis of apoptotic
cells and associated ERK signaling in macrophages. Journal of Cell Biology, 174, 547-556. https://doi.org/10.1083/jcb.200601030
Katsumoto, A., Takeuchi, H., Takahashi, K., & Tanaka, F. (2018). Microglia in Alzheimer’s disease: risk factors and inflammation. Front. Neurol., 9, 978. https://doi.org/10.3389/fneur.2018.00978
Mattson, M. P. (2004). Pathways toward and away from Alzheimer’s disease. Nature, 430, 631-639. https://doi.org/10.1038/nature02621
Menzies, F. M., Fleming, A., & Rubinsztein, D. C. (2015). Compromised autophagy and neurodegenerative diseases. Nature Reviews Neuroscience, 16, 345-347. https://doi.org/10.1038/nrn3961
Moghadam, F. H., Alaie, H., Karbalaie, K., Tanhaei, S., Esfahani, M. H. N., & Baharvand, H. (2009). Transplantation of primed or unprimed mouse embryonic stem cell-derived neural precursor cells improves cognitive function in Alzheimerian rats.
Differentiation, 78, 59-68. https://doi.org/10.1016/j.diff.2009.06.005
Moreira, P. I., Carvalho, C., Zhu, X., Smith, G., & Perry, G. (2010). Mitochondrial dysfunction is a trigger of Alzheimer’s disease pathophysiology. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1802, 2-10.
https://doi.org/10.1016/j.bbadis.2009.10.006
Nagele, R. G., D’Andrea, M. R., Lee, H., Venkataraman, V., & Wang, H.-Y. (2003). Astrocytes accumulate Aβ42 and give rise to astrocytic amyloid plaques in Alzheimer disease in brains. Brain Research, 971, 197-209. https://doi.org/10.1016/S0006-
8993(03)02361-8
Nimmerjahn, A., Kirchoff, F., & Helmchen, F. (2005). Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science, 308, 1314-1318. https://doi.org/10.1126/science.1110647
Nishiyama, A., Komitova, M., Suzuki, R., & Zhu, X. (2009). Polydendrocytes (NG2 cells): multifunctional cells with lineage plasticity. Nature Reviews Neuroscience, 10, 9-22. https://doi.org/10.1038/nrn2495
Vasic, V., Barth, K., & Schmidt, M. H. H. (2019). Neurodegeneration and neuro-regeneration—Alzheimer's disease and stem cell therapy. International Journal of Molecular Sciences, 20(17), 4272. https://doi.org/10.3390/ijms20174272
Wyss-Coray, T., & Rogers, J. (2012). Inflammation in Alzheimer disease—a brief review of the basic science and clinical literature. Cold Spring Harb. Perspect. Med., 2, a006346. doi: 10.1101/cshperspect.a006346