THE INFLUENCE OF MITOCHONDRIA IN ALZHEIMER DISEASE AND POSSIBLE ALTERNATIVE THERAPIES


THE INFLUENCE OF MITOCHONDRIA IN ALZHEIMER DISEASE AND POSSIBLE ALTERNATIVE THERAPIES


Ferro M1*, Graubard A1, Escalante P1, Channan G.1

1FG Scientifica and Science Department at Nutrition Formulators Inc., Miramar Florida


The epidemiology of Alzheimer’s disease (AD) is notable. North America and Western Europe have the most expressive rates of disease (6.4% and 5.4% at age 60), followed by Latin America (4.9%) and, finally China (4%). The most important fact is that head trauma increases the deposition of amyloid βeta (Aβ) and the expression of neuronal tau as well as diabetes. Obesityand trans fats also increase the risk of AD. However, virtually no current pharmacotherapy is approved for agitation / excitation caused by AD, the only purpose is maintaining the memory of those affected by this disease. There is substantial evidence that some dysfunctions in the mitochondria are involved in AD. Mitochondria are essential for neuronal function because the limited glycolytic metabolism of these cells makes them highly dependent on aerobic oxidative phosphorylation (OXPHOS) for their energy needs. Increased concentrations of ROS are known to result in molecular damage to the site where they are produced, triggering what science calls oxidative stress. Another no less important pathophysiological process in neurological disease is mitochondrial membrane cholesterol. New evidence indicates that the burden of mitochondrial cholesterol can influence mitochondrial function regardless of its conversion to pregnenolone or oxysterols, emerging as a key factor in the pathology of several neurological diseases associated with mitochondrial dysfunction, as in the case of AD. In this way, neurons are strictly dependent on the presence of healthy mitochondria, especially in the synapses where these organelles produce ATP and concentration of Ca2+ ions, fundamental processes for the implementation of neurotransmission and generation of membrane potential along the axon. Controlling ROS, as well as reducing the inflammatory cascade in neurons can be a good strategy in controlling the disease. The reduction of cholesterol in the external mitochondrial membrane may be another interesting path for the reentry of glutathione in the control of ROS, which occurs due to the imbalance in the metabolism of the mitochondrial respiratory chain seen in AD. In this review, we discuss the role of mitochondria in AD as well as alternative therapies for controlling this disease with specific herbal and nutraceuticals.


Keywords: Alzheimer disease; Mitochondria; Inflammation; Beta amyloid plaques; Cholesterol; Reactive oxygen species

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How to cite this article:
Ferro M, Graubard A, Escalante P, Channan G.. The Influence of Mitochondria in Alzheimer Disease and Possible Alternative Therapies. International Journal of Neuroscience Research, 2021; 5:12. DOI: 10.28933/ijnr-2021-04-0606


References

1. RIZZ L, ROSSET I, AND RORIZ-CRUZ M. Global Epidemiology of Dementia: Alzheimer’s and Vas-cular Types. Biomed Res Int. 2014; 2014: 908915.
2. QIU C, KIVIPELTO M, AND VON STRAUSS E. Epidemiology of Alzheimer’s disease: occurrence, determinants, and strategies toward intervention. Dialogues Clin Neurosci. 2009 Jun; 11(2): 111–128.
3. DE LA MONTE SM. Contributions of Brain Insulin Resistance and Deficiency in Amyloid-Related Neurodegeneration in Alzheimer’s Disease. Drugs. 2012 Jan 1; 72(1): 49–66.
4. SILVA MVF, LOURES CMG, ALVES LCV, DE SOUZA LC, BORGES KBG, AND CARVALHO MG. Alzheimer’s disease: risk factors and potentially protective measures. J Biomed Sci. 2019; 26: 33.
5. 5. KANDIMALLAA R, THIRUMALAAB V, AND REDDY PH. Is Alzheimer’s disease a Type 3 Di-abetes? A critical appraisal. Biochimica et Bio-physica Acta (BBA) – Molecular Basis of Disease. Volume 1863, Issue 5, May 2017, Pages 1078-1089.
6. CRAFT S. The Role of Metabolic Disorders in Alzheimer Disease and Vascular Dementia. Arch Neurol. 2009;66(3):300-305.
7. KELLAR D, AND CRAFT S. Brain insulin re-sistance in Alzheimer’s disease and related dis-orders: mechanisms and therapeutic approaches. The Lancet Neurology. VOLUME 19, ISSUE 9, P758-766, SEPTEMBER 01, 2020.
8. RUSSO EB. Cannabis Therapeutics and the Fu-ture of Neurology. Front Integr Neurosci. 2018 Oct 18;12:51.
9. IJAOPO EO. Dementia-related agitation: a review of non-pharmacological interventions and analysis of risks and benefits of pharmacotherapy. Transl Psychiatry. 2017 Oct; 7(10): e1250.
10. EL-HAYEK YH, WILEY RE, KHOURY CP, DAYA RP, BALLARD C, EVANS AR, et al. Tip of the Iceberg: Assessing the Global Socioeconomic Costs of Alzheimer’s Disease and Related De-mentias and Strategic Implications for Stakehold-ers. J Alzheimers Dis. 2019; 70(2): 323–341.
11. CENINI G, AND VOOS W. Mitochondria as Po-tential Targets in Alzheimer Disease Therapy: An Update. Front Pharmacol. 2019; 10: 902.
12. GRIMM A, FRIEDLAND K, AND ECKERT A. Mi-tochondrial dysfunction: the missing link between aging and sporadic Alzheimer’s disease. Bioger-ontology. 2016 Apr;17(2): 281- 96.
13. GUO L, TIAN J, AND DU H. Mitochondrial Dys-function and Synaptic Transmission Failure in Alzheimer’s Disease. J Alzheimers Dis.2017; 57(4):1071-1086.
14. RIDGE PG, AND KAUWE JSK. Mitochondria and Alzheimer’s Disease: the Role of Mitochondrial Genetic Variation. Curr Genet Med Rep. 2018;6(1):1-10.
15. MOREIRA PI, CARVALHO C, ZHUC X, SMITHC MA, AND PERRY G. Mitochondrial dysfunction is a trigger of Alzheimer’s disease pathophysiology. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease. Volume 1802, Issue 1, January 2010, Pages 2-10.
16. KANN O, AND KOVA´CS R. Mitochondria and neuronal activity. Am J Physiol Cell Physiol 292: C641–C657, 2007.
17. ZOROV DB, JUHASZOVA M, AND SOLLOTT SJ. Mitochondrial Reactive Oxygen Species (ROS) and ROS-Induced ROS Release. Physiol Rev. 2014 Jul; 94(3): 909–950.
18. SWERDLOW RH, BURNS JM, AND KHAN SM. The Alzheimer’s disease mitochondrial cascade hypothesis. J Alzheimers Dis. 2010;20 Suppl 2(Suppl 2):S265-79.
19. SWERDLOW RH, BURNS JM, AND KHAN SM. The Alzheimer’s Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives. Biochim Biophys Acta. 2014 Aug; 1842(8): 1219–1231.
20. BONDA DJ, WANG X, PERRY G, SMITH MA, AND ZHU X. Mitochondrial Dynamics in Alzhei-mer’s Disease Opportunities for Future Treatment Strategies. Drugs Aging. 2010 Mar 1; 27(3): 181–192.
21. 21. SILVA DF, SELFRIDGE JE, LU J, LEZI E, CARDOSO SM, AND SWERDLOW RH. Mito-chondrial abnormalities in Alzheimer’s disease: Possible targets for therapeutic intervention. Adv Pharmacol. 2012; 64: 83–126.
22. PAGANI L, AND ECKERT A. Amyloid-Beta Inter-action with Mitochondria. International Journal of Alzheimer’s Disease / 2011. 12 pages.
23. JENSEN MB, AND JASPER H. Mitochondrial proteostasis in the control of aging and longevity. Cell Metab. 2014 Aug 5;20(2):214-25.
24. ORTIZ JMP, AND SWERDLOW RH. Mitochondrial dysfunction in Alzheimer’s disease: Role in path-ogenesis and novel therapeutic opportunities. Br J Pharmacol. 2019 Sep; 176(18): 3489–3507.
25. HAWKING ZL. Alzheimer’s disease: the role of mitochondrial dysfunction and potential new ther-apies. The International Journal of Student Re-search, Volume 9, 2016.
26. 26. KHAN NA, GOVINDARAJ P, MEENA AK, AND THANGARAJ K. Mitochondrial disorders: Challenges in diagnosis & treatment. Indian J. Med Res. 2015 Jan; 141(1): 13–26.
27. MISSIROLI S, GENOVESE I, PERRONE M, VEZZANI B, VITTO VAV, AND GIORGI C. The Role of Mitochondria in Inflammation: From Cancer to Neurodegenerative Disorders. J Clin Med. 2020 Mar; 9(3): 740.
28. TAYLOR RW, DOUG M, AND TURNBULL DM. Mitochondrial DNA mutations in human disease. Nat Rev Genet. 2005 May; 6(5): 389–402.
29. WANG W, ZHAO F, MA X, PERRY G AND ZHU X. Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: recent advances. Molecular Neurodegeneration. (2020) 15:30.
30. MATTSON MP, GLEICHMANN M, AND CHENG A. Mitochondria in Neuroplasticity and Neurological Disorders. Neuron. 2008 Dec 10; 60(5): 748–766.
31. KASHYAP G, BAPAT D, DAS D, GOWAIKAR R, AMRITKAR RE, RANGARAJAN G, et al. Synapse loss and progress of Alzheimer’s disease – A network model. Scientific Reports. 6555 (2019).
32. MANDAL A, AND DRERUP CM. Axonal Transport and Mitochondrial Function in Neurons. Front Cell Neurosci. 2019; 13: 373.
33. SHENG Z, AND CAI Q. Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration. Nat Rev Neurosci. 2012 Feb; 13(2): 77–93.
34. HILLA RL, KULBEABINDRAPAL JR, SINGH IN, WANGA JA, HALL ED. Synaptic Mitochondria are More Susceptible to Traumatic Brain Inju-ry-induced Oxidative Damage and Respiratory Dysfunction than Non-synaptic Mitochondria. Neuroscience. Volume 386, 21 August 2018, Pages 265-283.
35. HOLLENBECK PJ, SAXTON WM. The axonal transport of mitochondria. J Cell Sci. 2005 Dec 1;118(Pt 23):5411-9.
36. KANN O, AND KOVA´CS R. Mitochondria and neuronal activity. Am J Physiol Cell Physiol 292: C641–C657, 2007. First published November 8, 2006.
37. ZOROVA LD, POPKOV VA, PLOTNIKOV EY, SILACHEV DN, PEVZNER IB, JANKAUSKAS SS, et al. Mitochondrial membrane potential. Anal Bi-ochem. 2018 Jul 1; 552: 50–59.
38. SERGIO DI MEO, TANEA T. REED, PAOLA VENDITTI, AND VICTOR MANUEL VICTOR. Role of ROS and RNS Sources in Physiological and Pathological Conditions. Oxid Med Cell Longev. 2016; 2016: 1245049.
39. GASPAROVIC AC, ZARKOVIC N, ZARKOVIC K, SEMEN K, KAMINSKYY D, YELISYEYEVA O, et al. Biomarkers of oxidative and nitro-oxidative stress: conventional and novel approaches. Br J Pharmacol. 2017 Jun;174(12):1771-1783.
40. MASSAAD CA, AND KLANN E. Reactive Oxygen Species in the Regulation of Synaptic Plasticity and Memory. Antioxid Redox Signal. 2011 May 15; 14(10): 2013–2054.
41. UTTARA B, SINGH AV, ZAMBONI P, AND MA-HAJAN RT. Oxidative Stress and Neurodegenera-tive Diseases: A Review of Upstream and Down-stream Antioxidant Therapeutic Options. Curr Neuropharmacol. 2009 Mar; 7(1): 65–74.
42. COBLEY JN, FIORELLO ML, AND BAILEY DM. 13 reasons why the brain is susceptible to oxidative stress. Redox Biol. 2018 May; 15:490-503.
43. GIBSON GE, AND SHI Q. A mitocentric view of Alzheimer’s disease suggests multi-faceted treatments. J Alzheimers Dis. 2010;20 Suppl 2(0 2):S591-607.
44. MARCUS C, MENA E, AND SUBRAMANIAM R M. Brain PET in the Diagnosis of Alz-heimer’s Disease. Clin Nucl Med. 2014 Oct; 39(10): e413–e426.
45. MOSCONI L. Glucose metabolism in normal aging and Alzheimer’s disease: Methodological and physiological considerations for PET studies. Clin Transl Imaging. 2013 Aug; 1(4): 10.1007/s40336-013-0026-y.
46. DU H, GUO L, YAN S, SOSUNOV AA, MCKHANN GM, AND YAN SS. Early deficits in synaptic mi-tochondria in an Alzheimer’s disease mouse model. Proc Natl Acad Sci U S A. 2010 Oct 26; 107(43): 18670–18675.
47. YAOA J, AND BRINTON RD. Targeting Mitochon-drial Bioenergetics for Alzheimer’s Prevention and Treatment. Curr Pharm Des. 2011; 17(31): 3474–3479.
48. CARDOSO SM, M PROENÇA T, SANTOS S, SANTANA I, AND OLIVEIRA CR. Cytochrome c oxidase is decreased in Alzheimer’s disease platelets. Neurobiol Aging. 2004 Jan;25(1): 105-10.
49. YANG S, KREUTZBERGER AJB, LEE J, KIESSLING V, AND LUKAS K. Tamm. The Role of Cholesterol in Membrane Fusion. Chem Phys Li-pids. 2016 Sep; 199: 136–143.
50. ORTH M, AND BELLOSTA S. Cholesterol: Its Regulation and Role in Central Nervous System Disorders. Cholesterol. 2012; 2012: 292598.
51. TRACEY TJ, STEYN FJ, ERNST J. WOLVETANG EJ AND NGO ST. Neuronal Lipid Metabolism: Multiple Pathways Driving Functional Outcomes in Health and Disease. Front. Mol. Neurosci., 23 January 2018.
52. JIE HU J, ZHANG Z, SHEN W, AND AZHA S. Cellular cholesterol delivery, intracellular processing and utilization for biosynthesis of steroid hormones. Nutr Metab (Lond). 2010; 7: 47.
53. MANNA PR, STETSON CL, SLOMINSKI AT, AND PRUITT K. Role of the steroidogenic acute regu-latory protein in health and disease. Endocrine. 2016 Jan; 51(1): 7–21.
54. TORRES S, GARCÍA-RUIZ CM, AND FERNAN-DEZ-CHECA JC. Mitochondrial Cholesterol in Alzheimer’s Disease and Niemann–Pick Type C Disease. Front Neurol. 2019; 10: 1168.
55. GARCIA-RUIZ C, MARI M, COLELL A, MORALES A, CABALLERO F, MONTERO J. et al. Mito-chondrial cholesterol in health and disease. Histol Histopathol (2009) 24: 117-132.
56. RIBAS V, GARCÍA-RUIZ C, AND FERNÁNDEZ- CHECA JC. Glutathione and mitochondria. Front Pharmacol. 2014; 5: 151.
57. 57. ONYANGO IG. Modulation of mitochondrial bioenergetics as a therapeutic strategy in Alzhea. imer’s disease. Neural Regen Res. 2018 Jan;13 (1): 19–25.
58. MAST N, LIN JB, ANDERSON KW, BJORKHEM I, AND PIKULEVA IA. Transcriptional and post-translational changes in the brain of mice de-ficient in cholesterol removal mediated by cyto-chrome P450 46A1 (CYP46A1). PLoS One. 2017 Oct 26;12(10): e0187168.
59. DJELTI F, BRAUDEAU J, HUDRY E, DHENAIN M, VARIN J, BIÈCHE I. et al. CYP46A1 inhibition, brain cholesterol accumulation and neurodegen-eration pave the way for Alzheimer’s disease.
60. PETROV AM, AND PIKULEVA IA. Cholesterol 24-Hydroxylation by CYP46A1: Benefits of Mod-ulation for Brain Diseases. Neurotherapeutics. 2019 Jul; 16(3): 635–648.
61. BALLATORI N, KRANCE SM, NOTENBOOM S, SHI S, TIEU K, AND HAMMOND CL. Glutathione dysregulation and the etiology and progression of human diseases. Biol Chem. 2009 Mar; 390(3): 191–214.
62. POCERNICHA CB, AND BUTTERFIELD DA. El-evation of glutathione as a therapeutic strategy in Alzheimer disease. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease. Volume 1822, Issue 5, May 2012, Pages 625-630.
63. BUTTERFIELD DA, HARDAS SS, AND LANGE MLB. Oxidatively Modified Glyceraldehyde-3- Phosphate Dehydrogenase (GAPDH) and Alz-heimer Disease: Many Pathways to Nerrode-
a. generation. J Alzheimers Dis. 2010; 20(2): 369– 393.
64. HAN C, LIU Y, DAI R, ISMAIL N, SU W, AND LI B. Ferroptosis and Its Potential Role in Human Dis-eases. Front Pharmacol. 2020; 11: 239.
65. GIUSTARINI D, GALVAGNI F, DONNE ID, MIL-ZANI A, SEVERI FM, SANTUCCI A. et al. N-acetylcysteine ethyl ester as GSH enhancer in human primary endothelial cells: A comparative study with other drugs. Free Radic Biol Med. 2018 Oct; 126:202-209.
66. JOSHI G, HARDAS S, SULTANA R, ST CLAIR DK, VORE M, AND BUTTERFIELD DA. Glutathione elevation by gamma?glutamyl cysteine ethyl ester as a potential therapeutic strategy for preventing oxidative stress in brain mediated by in vivo ad-ministration of adriamycin: Implication for che-mobrain. J Neurosci Res. 2007 Feb 15;85(3):497-503.
67. FARR SA, POON HF, DOGRUKOL-AK D, DRAKE J, BANKS WA, EYERMAN E. et al. The antioxi-dants alpha-lipoic acid and N- acetylcysteine re-verse memory impairment and brain oxia. dative stress in aged SAMP8 mice. J Neu-roche-m. 2003 Mar;84(5):1173-83.
68. TARDIOLO G, BRAMANTI P, AND MAZZON E. Overview on the Effects of N-Acetylcysteine in Neurodegenerative Diseases. Molecules. 2018 Dec; 23(12): 3305.
69. MEDINA S, MARTINEZ-BANACLOCHA M AND HERNANZ A. Antioxidants Inhibit the Human Cor-tical Neuron Apoptosis Induced by Hydrogen Peroxide, Tumor Necrosis Factor Alpha, Dopamine and Beta-amyloid Peptide 1-42. Free Radical Re-search (2002) 36(11):1179-84.
70. BRAIDY N, ZARKA M, JUGDER B, WELCH J, JAYASENA T, CHAN DKY. et al. The Precursor to Glutathione (GSH), γ-Glutamylcysteine (GGC), Can Ameliorate Oxidative Damage and Neuroin-flammation Induced by Aβ40 Oligomers in Human Astrocytes. Front Aging Neurosci. 2019; 11: 177.
71. LOK J, LEUNG W, ZHAO S, PALLAST S, VAN LEYEN K, GUO S. et al. Gamma- glutamylcys-teine ethyl ester protects cerebral endothelial cells during injury and decreases blood- brain-barrier permeability after experimental brain trauma. J Neurochem. 2011 Jul; 118(2): 248–255.
72. ZARKA M. AND BRIDGE W. Oral administration of Gamma-glutamylcysteine increases intracellular glutathione levels above homeostasis in a ran-domised human trial pilot study. January 2017 Redox Biology 11(C).
73. WANG W, TAN M, YU J, AND TAN L. Role of pro-inflammatory cytokines released from micro-glia in Alzheimer’s disease. Ann Transl Med. 2015 Jun; 3(10): 136.
74. GONZÁLEZ-REYES RE, NAVA-MESA MO, VARGAS-SÁNCHEZ K, ARIZA-SALAMANCA D, AND MORA-MUÑOZ L. Involvement of Astrocytes in Alzheimer’s Disease from a Neuroinflammatory and Oxidative Stress Perspective. Front Mol Neurosci. 2017; 10: 427.
75. PIZZURRO DM, DAO K, AND COSTA LG. Astro-cytes protect against diazinon- and diazox-on-induced inhibition of neurite outgrowth by reg-ulating neuronal glutathione. Toxicology. 2014 Apr 6; 318: 59–68.
76. DANEMAN R, AND PRAT A. The Blood–Brain Barrier. Cold Spring Harb Perspect Biol. 2015 Jan; 7(1): a020412.
77. BÉLANGER M. The role of astroglia in neuropro-tection. Dialogues Clin Neurosci. 2009 Sep; 11(3): 281–295.
78. KULAS JA, FRANKLIN WF, SMITH NA, MANO-CHA GD, PUIG KL, NAGAMOTO- COMBS K, et al. Ablation of amyloid precursor protein increases insulin-degrading enzyme levels and activity in brain and peripheral tissues. Am J Physiol Endocrinol Metab. 2019 Jan 1;316(1):E10 6-E120.
79. BARANELLO RJ, BHARANI KL, PADMARAJU V, CHOPRA N, LAHIRI DK, GREIG NH, et al. Amy-loid-Beta Protein Clearance and Degradation (ABCD) Pathways and their Role in Alzheimer’s Disease. Curr Alzheimer Res. 2015; 12(1): 32–46.
80. NAGARKATTI P, PANDEY R, RIEDER SA, HEGDE VL, AND NAGARKATTI M. Cannabinoids as novel anti?inflammatory drugs. Future Med Chem. 2009 Oct; 1(7): 1333–1349.
81. O’SULLIVAN SE. An update on PPAR activation by cannabinoids. Br J Pharmacol. 2016 Jun; 173(12): 1899–1910.
82. 82. BURSTEIN S. PPAR-γ: A nuclear receptor with affinity for cannabinoids. Life Sciences (2005). 77(14):1674-84.
83. HEGDE VL, SINGH UP, NAGARKATTI PS, NA-GARKATTI M. Critical Role of Mast Cells and Peroxisome Proliferator?Activated Receptor γ in the Induction of Myeloid-Derived Suppressor Cells by Marijuana Cannabidiol In Vivo. J Immunol. 2015 Jun 1;194(11):5211-22.
84. KOZELA E, PIETR M, JUKNAT A, RIMMERMAN N, LEVY R, AND VOGEL Z. Cannabinoids Δ9-Tetrahydrocannabinol and Cannabidiol Differ-entially Inhibit the Lipopolysaccharide-activated NF-κB and Interferon-β/STAT Proinflammatory Pathways in BV-2 Microglial Cells. J Biol Chem. 2010 Jan 15; 285(3): 1616–1626).
85. NICHOLS JM, AND KAPLAN BLF. Immune Re-sponses Regulated by Cannabidiol. Cannabis Cannabinoid Res. March 2020; 5(1): 12–31.
86. AMOR S, LAN P, VOGEL DYS, BREUR M, VALK P, BAKER D, AND NOORT JM. Inflammation in neurodegenerative diseases – an update.
87. KOZELA E, PIETR M, JUKNAT A, RIMMERMAN N, LEVY R, AND VOGEL Z. Cannabinoids Delta (9) -tetrahydrocannabinol and cannabidiol differentially inhibit the lipopolysaccharide- activated NF-kappa B and interferon-beta/STAT proinflammatory pathways in BV-2 microglial cells. J Biol Chem. 2010 Jan 15;285(3): 1616- 26.
88. HIND WH, ENGLAND TJ, AND O’SULLIVAN SE. Cannabidiol protects an in vitro model of the blood-brain barrier from oxygen-glucose depriva-tion via PPARγand 5-HT1A receptors. Br J Phar-macol. 2016 Mar;173(5):815-25.
89. BIH CI, CHEN T, NUNN AVW, BAZELOT M, DALLAS M, AND WHALLEY BJ. Molecular Targets of Cannabidiol in Neurological Disorde s. Neurotherapeutics. 2015 Oct; 12(4): 699–730.
90. GARCÍA-ARENCIBIA M, GONZÁLEZ S, DE LAGO E, RAMOS JA, MECHOULAM R, FER-NÁNDEZ-RUIZ J. Evaluation of the neuroprotec-tive effect of cannabinoids in a rat model of Park-inson’s disease: importance of antioxidant and cannabinoid receptor- independent properties. Brain Res. 2007 Feb 23;1134(1):162-70.
91. RYAN D, DRYSDALE AJ, LAFOURCADE C, PERTWEE RG, AND PLATT B. Cannabidiol Tar-gets Mitochondria to Regulate Intracellular Ca2+ Levels. J Neurosci. 2009 Feb 18; 29(7): 2053–2063.
92. YU SB, AND PEKKURNAZ G. Mechanisms Or-chestrating Mitochondrial Dynamics for Energy Homeostasis. J Mol Biol. 2018 Oct 19; 430(21): 3922–3941.
93. 93. SODHI RK, AND SINGH N. Retinoids as po-tential targets for Alzheimer’s disease. Pharmacol Biochem Behav. 2014 May;120:117- 23.
94. CHANDRA V, HUANG P, HAMURO Y, RAGHURAM S, WANG Y, BURRIS TP, et al. Structure of the intact PPAR-γ–RXR-α nuclear receptor complex on DNA. Nature. 2008 Nov 20; 456(7220): 350–356.
95. ZIOUZENKOVA O, AND PLUTZKY J. Retinoid metabolism and nuclear receptor responses: New insights to coordinated regulation of the PP –AR-RXR complex. FEBS Lett. 2008 Jan 9; 582 (1):32-8.
96. HUANG P, CHANDRA V, AND RASTINEJAD F. Retinoic Acid Actions Through Mammalian Nuclear Receptors. Chem Rev. 2014 Jan 8; 114(1): 233–254.
97. DAWSON MI, AND XIA Z. The Retinoid X Recep-tors and Their Ligands. Biochim Biophys Acta. 2012 Jan; 1821(1): 21–56.
98. DING Y, QIAO A, WANG Z, GOODWIN JS, LEE E, BLOCK ML. Et al. Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Defi-cits in an Alzheimer’s Disease Transgenic Mouse Model. J Neurosci. 2008 Nov 5; 28(45): 11622–11634.
99. KAPOOR A, WANG B, HSU W, CHANG M, LIANG S, AND LIAO Y. Retinoic Acid-Elicited RARα/RXRαSignaling Attenuates AβProduction by Directly Inhibiting γ-Secretase-Mediated Cleavage of Amyloid Precursor Protein. ACS Chem Neurosci. 2013 Jul 17; 4(7): 1093–1100.
100. LIN Y, LIEN L, YEH T, WU H. 9-cis retinoic acid induces retinoid X receptor localized to the mito-chondria for mediation of mitochondrial transcrip-tion. Biochemical and Biophysical Research Communications 377(2):351-4.
101. SABATO DD, QUAN N, AND GODBOUT JP. Neuroinflammation: The Devil is in the Details. J Neurochem. 2016 Oct; 139(Suppl 2): 136–153.
102. CHEN W, ZHANG X, AND HUANG W. Role of neuroinflammation in neurodegenerative diseases (Review). Mol Med Rep. 2016 Apr;13(4):3391-6.
103. 103.GEROVSKA D, IRIZAR H, OTAEGI D, FERRER I, DE MUNAIN AL, AND ARAÚZO-BRAVO MJ. Genealogy of the neuro-degenerative diseases based on a meta-analysis of age-stratified incidence data. Scientific Reports volume 10, Article number: 18923 (2020).
104. HICKMAN S, IZZY S, SEN P, MORSETT L, AND KHOURY J. Microglia in neurodegeneration. Nat Neurosci. 2018 Oct; 21(10): 1359–1369.
105. KIM B, KOPPULA S, HONG S, JEON S, KWON J, HWANG B. et al. Regulation of Microglia Activity by Glaucocalyxin?A: Attenuation of Lipopolysac-charide-Stimulated Neuroinflammation through NF-κB and p38 MAPK Signaling Pathways. PLoS One. 2013; 8(2): e55792.
106. HARRY GJ, AND KRAFT AD. Neuroinflammation and Microglia: Considerations and approaches for neurotoxicity assessment. Expert Opin Drug Metab Toxicol. 2008 Oct; 4(10): 1265–1277.
107. HINOJOSA AE, GARCIA-BUENO B, LEZA JC, AND MADRIGAL JLM. CCL2/MCP-1 modulation of microglial activation and proliferation. Journal of Neuroinflammation volume 8, Article number: 77 (2011).
108. KRAFT AD, AND HARRY GJ. Features of Mi-croglia and Neuroinflammation Relevant to Envi-ronmental Exposure and Neurotoxicity. Int J En-viron Res Public Health. 2011 Jul; 8(7): 2980–3018.
109. YANG C, YU L, KONG L, MA R, ZHANG J, ZHU Q, et al. Pyrroloquinoline Quinone (PQQ) Inhibits Lipopolysaccharide Induced Inflammation in Part via Downregulated NF-κB and p38/JNK Activation in Microglial and Attenuates Microglia Activation in Lipopolysaccharide Treatment Mice. PLoS One. 2014; 9(10): e109502.
110. ZHANG Y, FEUSTEL PJ, AND KIMELBERG HK. Neuroprotection by pyrroloquino-line quinone (PQQ) in reversible middle cerebral artery occlusion in the adultrat. Brain Res (2006) 13;1094(1):200–6.
111. LIU Z, SUN C, TAO R, AND XU X. Pyrroloquino-line Quinone Decelerates Rheumatoid Arthritis Progression by Inhibiting Inflammatory Responses and Joint Destruction via Modulating NF-κB and MAPK Pathways. August 2015Inflammation 39(1).
112. ZHANG Q, ZHOU J, SHEN M, XU H, YU S, CHENG Q, et al. Pyrroloquinoline Quinone Inhibits Rotenone-Induced Microglia Inflammation by En-hancing Autophagy. Molecules 2020, 25, 4359.
113. JOHNSON S, AND IMAI S. NAD + biosynthesis, aging, and disease. Version 1. F1000Res. 2018; 7: 132.
114. PODDAR SK, SIFAT AE, HAQUE S, NAHID NA, CHOWDHURY S, AND MEHED I. Nicotinamide Mononucleotide: Exploration of Diverse Therapeu-tic Applications of a Potential Molecule. Biomol-ecules. 2019 Jan; 9(1): 34.
115. YANG Y, AND SAUVE AA. NAD+ metabolism: Bioenergetics, signaling and manipulation for therapy. Biochim Biophys Acta. 2016 Dec; 1864(12): 1787–1800.
116. LONG AN, OWENS K, SCHLAPPAL AE, AND KRISTIAN T. Effect of nicotinamide mononucleo-tide on brain mitochondrial respiratory deficits in an Alzheimer’s disease- relevant murine model. March 2015. BMC Neurology 15(1):272.
117. HONG W, MO F, ZHANG Z, HUANG M, AND WEI X. Nicotinamide Mononucleotide: A Promising Molecule for Therapy of Diverse Diseases by Targeting NAD+ Metabolism. Front Cell Dev Biol. 2020; 8: 246.
118. ZEMEK F, DRTINOVA L, NEPOVIMOVA E, SEPSOVA V, KORABECNY J, KLIMES J, et al. Outcomes of Alzheimer’s disease therapy with acetylcholinesterase inhibitors and memantine. Expert Opin Drug Saf. 2014 Jun;13(6):759-74.
119. CANTÓ C, MENZIES K, AND AUWERX J. NAD+ metabolism and the control of energy homeostasis – a balancing act between mitochondria and the nucleus. Cell Metab. 2015 Jul 7; 22(1): 31–53.
120. BERMAN SB, PINEDA FJ, AND HARDWICK JM. Mitochondrial fission and fusion dynamics: the long and short of it. Cell Death & Differentiation volume 15, pages1147–1152(2008).
121. REDDY PH. Inhibitors of Mitochondrial Fission as a Therapeutic Strategy for Diseases with Oxidative Stress and Mitochondrial Dysfunction. J Alz-heimers Dis. 2014 Jan 1; 40(2): 245–256.
122. WANG X, HU X, YANG Y, TAKATA T, AND SA-KURAI T. Nicotinamide mononucleotide protects against β-amyloid oligomer-induced cognitive im-pairment and neuronal death. Brain Res. 2016; 1643: 1–9.
123. QIN W, HAROUTUNIAN V, KATSEL P, CA RDOZO CP, AND HO L. PGC-1α Expression Decreases in the Alzheimer Disease Brain as a Function of Dementia. Arch. Neurol. 2009; 66: 352–361.
124. MURPHY MP, AND LEVINE H. Alzheimer’s Disease and the β-Amyloid Peptide. J Alzheimers Dis. 2010 Jan; 19(1): 311.
125. SAHARAN S, AND MANDAL PK. The emerging role of glutathione in Alzheimer’s disease. J Alz-heimers Dis. 2014;40(3):519-29.
126. CORONAA JC, AND DUCHEN MR. PPARγas a therapeutic target to rescue mitochondrial function in neurological disease. Free Radic Biol Med. 2016 Nov; 100: 153–163.
127. GENG L, ZHANG T, LIU W, AND CHEN Y. Inhi-bition of miR-128 Abates Aβ-Mediated Cytotoxicity by Targeting PPAR-γvia NF-κB Inactivation in Primary Mouse Cortical Neurons and Neuro2a Cells. Yonsei Med J. 2018 Nov;59(9): 1096-1106.
128. BRIGHT JJ, KANAKASABAI S, CHEARWAE W, AND CHAKRABORTY S. PPAR Regulation of In-flammatory Signaling in CNS Diseases. PAR Re-search. Volume 2008, Article ID 658520, 12 pages.
129. VEPSÄLÄINEN S, PARKINSON M, HELISALMI S, MANNERMAA A, SOININEN H, TANZI RE, et al. Insulin‐degrading enzyme is genetically associ-ated with Alzheimer’s disease in the Finnish pop-ulation. J Med Genet. 2007 Sep; 44(9): 606–608.
130. VEKRELLIS K, YE Z, QIU WQ, WALSH D, HARTLEY D, CHESNEAU V, et al. Neurons Reg-ulate Extracellular Levels of Amyloid β-Protein via Proteolysis by Insulin-Degrading Enzyme. J Neu-rosci. 2000 Mar 1; 20(5): 1657–1665.
131. LEAL MC, MAGNANI N, VILLORDO S, BUSLJE CM, EVELSON P, CASTAÑO EM, et al. Tran-scriptional Regulation of Insulin-degrading Enzyme Modulates Mitochondrial Amyloid β (Aβ) Peptide Catabolism and Functionality. J Biol Chem. 2013 May 3; 288(18): 12920–12931.