Skip to main content Accessibility help
×
Hostname: page-component-cd9895bd7-mkpzs Total loading time: 0 Render date: 2024-12-27T05:12:58.515Z Has data issue: false hasContentIssue false

7 - Role of Animal Models in Alzheimer’s Disease Drug Development

from Section 2 - Non-clinical Assessment of Alzheimer’s Disease Candidate Drugs

Published online by Cambridge University Press:  03 March 2022

Jeffrey Cummings
Affiliation:
University of Nevada, Las Vegas
Jefferson Kinney
Affiliation:
University of Nevada, Las Vegas
Howard Fillit
Affiliation:
Alzheimer’s Drug Discovery Foundation
Get access

Summary

Animal model systems play a fundamental role in the development and evaluation of novel treatments for Alzheimer’s disease (AD). The examination of safety and tolerability in animal models is a necessary first step prior to any human clinical trials. Equally important, preclinical testing of novel therapeutics in disease relevant models is required for the determination if a potential therapeutic should advance. There are a number of important considerations in the preclinical workflow that range from selection of the most appropriate animal model related to drug mechanism of action, as well as what AD-relevant measures are to be evaluated to determine if a candidate therapy should advance. In this chapter we highlight the process of preclinical animal model testing for novel therapeutics in AD, as well as detail several of the models utilized and the measures relevant to AD. We also include the emerging approaches to provide better AD animal models (MODEL-AD) as well as emerging approaches to refine the process of identifying new treatments (TREAT-AD).

Type
Chapter
Information
Alzheimer's Disease Drug Development
Research and Development Ecosystem
, pp. 73 - 94
Publisher: Cambridge University Press
Print publication year: 2022

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Zhao, M, Lepak, AJ, Andes, DR. Animal models in the pharmacokinetic/pharmacodynamic evaluation of antimicrobial agents. Bioorg Med Chem 2016; 24: 6390–400.CrossRefGoogle ScholarPubMed
Ambrose, PG, Bhavnani, SM, Rubino, CM, et al. Pharmacokinetics–pharmacodynamics of antimicrobial therapy: it’s not just for mice anymore. Clin Infect Dis 2007; 44: 7986.Google Scholar
Fitten, LJ, Flood, JF, Baxter, CF, Tachiki, KH, Perryman, K. Long-term oral administration of memory-enhancing doses of tacrine in mice: a study of potential toxicity and side effects. J. Gerontol 1987; 42: 681–5.CrossRefGoogle ScholarPubMed
Scearce-Levie, K, Sanchez, PE, Lewcock, JW. Leveraging preclinical models for the development of Alzheimer disease therapeutics. Nat Rev Drug Discov 2020; 19: 447–62.CrossRefGoogle ScholarPubMed
Fan, L, Mao, C, Hu, X, et al. New insights into the pathogenesis of Alzheimer’s disease. Front Neurol 2020; 10:1312.CrossRefGoogle ScholarPubMed
Kinney, JW, Bemiller, SM, Murtishaw, AS, et al. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement (N Y) 2018; 4: 575–90.Google ScholarPubMed
Schenk, D, Barbour, N, Dunn, W, et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999; 400: 173.Google Scholar
Orgogozo, J-M, Gilman, S, Dartigues, J-F, et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 2003; 61: 4654.CrossRefGoogle Scholar
Nicoll, JAR, Wilkinson, D, Holmes, C, et al. Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report. Nat Med 2003; 9: 448–52.CrossRefGoogle ScholarPubMed
Fandos, N, Pérez-Grijalba, V, Pesini, P, et al. Plasma amyloid β42/40 ratios as biomarkers for amyloid β cerebral deposition in cognitively normal individuals. Alzheimers Dement (Amst) 2017; 8: 179–87.Google Scholar
Moore, BD, Martin, J, de Mena, L, et al. Short Aβ peptides attenuate Aβ42 toxicity in vivo. J Exp Med 2018; 215: 283301.CrossRefGoogle ScholarPubMed
Salazar, A, Leisgang, A, Ortiz, A, Kinney, J. Dementia insights: what do animal models of Alzheimer’s disease tell us? Pract Neurol 2019;July/August:23–34.Google Scholar
Janelidze, S, Stomrud E, Smith R, et al. Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer’s disease. Nat Commun 2020; 11: 1683.CrossRefGoogle ScholarPubMed
Thijssen, EH, La Joie R, Wolf A, et al. Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Nat Med 2020; 26: 387–97.CrossRefGoogle ScholarPubMed
Van Dam, D, De Deyn, PP. Animal models in the drug discovery pipeline for Alzheimer’s disease. Br J Pharmacol 2011; 164: 1285–300.Google Scholar
Cummings, J, Lee, G, Ritter, A, Sabbagh, M, Zhong, K. Alzheimer’s disease drug development pipeline: 2020. Alzheimers Dement (N Y) 2020; 6: e12050.CrossRefGoogle ScholarPubMed
Sterniczuk, R, Antle, MC, LaFerla, FM, Dyck, RH. Characterization of the 3×Tg-AD mouse model of Alzheimer’s disease: part 2. Behavioral and cognitive changes. Brain Res 2010; 1348: 149–55.Google Scholar
Martinez-Coria, H, Green, KN, Billings, LM, et al. Memantine improves cognition and reduces Alzheimer’s-like neuropathology in transgenic mice. Am J Pathol 2010; 176: 870–80.Google Scholar
Fiebich, BL, Batista, CRA, Saliba, SW, Yousif, NM, de Oliveira, ACP . Role of microglia TLRs in neurodegeneration. Front Cell Neurosci 2018; 12 : 329.Google Scholar
Zhao, J, Bi, W, Xiao, S, et al. Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice. Sci Rep 2019; 9: 5790.Google Scholar
Weintraub, MK, Kranjac, D, Eimerbrink, MJ, et al. Peripheral administration of poly I:C leads to increased hippocampal amyloid-beta and cognitive deficits in a non-transgenic mouse. Behav Brain Res 2014; 266: 183–7.CrossRefGoogle Scholar
Walker, DG, Tang, TM, Lue, L-F. Increased expression of toll-like receptor 3, an anti-viral signaling molecule, and related genes in Alzheimer’s disease brains. Exp Neurol 2018; 309: 91106.CrossRefGoogle ScholarPubMed
Alzheimer’s Association. 2020 Alzheimer’s disease facts and figures. Alzheimers Dement 2020; 16: 391460.Google Scholar
Yeoman, M, Scutt, G, Faragher, R. Insights into CNS ageing from animal models of senescence. Nat Rev Neurosci 2012; 13: 435–45.CrossRefGoogle ScholarPubMed
Morley, JE, Farr, SA, Kuma, VB, Armbrecht, HJ. The SAMP8 mouse: a model to develop therapeutic interventions for Alzheimer’s disease. Curr Pharm Des 2012; 18: 1123–30.CrossRefGoogle Scholar
Carroll, JC, Roasrio, ER, Chang, L, et al. Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3×Tg-AD mice. J Neurosci 2007; 27: 13357–65.CrossRefGoogle Scholar
Palm, R, Chang, J, Blair, J, et al. Down-regulation of serum gonadotropins but not estrogen replacement improves cognition in aged-ovariectomized 3×Tg AD female mice. J Neurochem 2014; 130: 115–25.CrossRefGoogle ScholarPubMed
Rolo, AP, Palmeira, CM. Diabetes and mitochondrial function: role of hyperglycemia and oxidative stress. Toxicol Appl Pharmacol 2006; 212: 167–78.Google Scholar
Murtishaw, AS, Hearney CF, Bolton MM, et al. Intermittent streptozotocin administration induces behavioral and pathological features relevant to Alzheimer’s disease and vascular dementia. Neuropharmacology 2018; 137: 164–77.Google Scholar
Candeias, E, Duarte, AI, Carvalho, C, et al. The impairment of insulin signaling in Alzheimer’s disease. IUBMB Life 2012; 64: 951–7.CrossRefGoogle ScholarPubMed
Dineley, KT, Jahrling, JB, Denner, L. Insulin resistance in Alzheimer’s disease. Neurobiol Dis 2014; 72: 92103.Google Scholar
Lee, Y, Kim, Y-H, Park, SJ, et al. Insulin/IGF signaling-related gene expression in the brain of a sporadic Alzheimer’s disease monkey model induced by intracerebroventricular injection of streptozotocin. J Alzheimers Dis 2014; 38: 251–67.Google ScholarPubMed
Yeo, H-G, Lee, Y, Jeon, CY, et al. Characterization of cerebral damage in a monkey model of Alzheimer’s disease induced by intracerebroventricular injection of streptozotocin. J Alzheimers Dis 2015; 46: 9891005.CrossRefGoogle Scholar
Bauzon, J, Lee, G, Cummings, J. Repurposed agents in the Alzheimer’s disease drug development pipeline. Alzheimers Res Ther 2020; 12: 98.Google Scholar
Knight, EM, Martins, VA, Gümüsgöz, S, Allan, SM, Lawrence, CB. High-fat diet-induced memory impairment in triple-transgenic Alzheimer’s disease (3×TgAD) mice is independent of changes in amyloid and tau pathology. Neurobiol Aging 2014; 35: 1821–32.CrossRefGoogle Scholar
Bracko, O, Vinarcsik, LK, Cruz, Hernández JC, et al. High fat diet worsens Alzheimer’s disease-related behavioral abnormalities and neuropathology in APP/PS1 mice, but not by synergistically decreasing cerebral blood flow. Sci Rep 2020; 10: 9884.CrossRefGoogle Scholar
Rollins, CPE, Gallion, D, Kong, V, et al. Contributions of a high-fat diet to Alzheimer’s disease-related decline: A longitudinal behavioural and structural neuroimaging study in mouse models. Neuroimage Clin 2019; 21: 101606.Google Scholar
Bhat, NR, Thirumangalakudi, L. Increased tau phosphorylation and impaired brain insulin/IGF signaling in mice fed a high fat/high cholesterol diet. J Alzheimers Dis 2013; 36: 781–9.Google Scholar
Busquets, O, Ettcheto, M, Pallàs, M, et al. Long-term exposition to a high fat diet favors the appearance of β-amyloid depositions in the brain of C57BL/6 J mice. A potential model of sporadic Alzheimer’s disease. Mech Ageing Dev 2017; 162: 3845.Google Scholar
Pugazhenthi, S, Qin, L, Reddy, PH. Common neurodegenerative pathways in obesity, diabetes, and Alzheimer’s disease. Biochim Biophys Acta 2017; 1863: 1037–45.Google ScholarPubMed
Prüßing, K, Voig, A, Schulz, JB. Drosophila melanogaster as a model organism for Alzheimer’s disease. Mol Neurodegener 2013; 8: 35.Google Scholar
Tan, FHP, Azzam, G. Drosophila melanogaster: Deciphering Alzheimer’s disease. Malays J Med Sci 2017; 24: 620.Google Scholar
Drummond, E, Wisniewski, T. Alzheimer’s disease: experimental models and reality. Acta Neuropathol 2017; 133: 155–75.CrossRefGoogle Scholar
Callahan, PM, Hutchings, EJ, Kille, NJ, Chapman, JM, Terry, AV. Positive allosteric modulator of α7 nicotinic-acetylcholine receptors, PNU-120596 augments the effects of donepezil on learning and memory in aged rodents and non-human primates. Neuropharmacology 2013; 67: 201–12.Google Scholar
Vardigan, JD, Cannon, CE, Puri, V, et al. Improved cognition without adverse effects: novel M1 muscarinic potentiator compares favorably to donepezil and xanomeline in rhesus monkey. Psychopharmacology (Berl) 2015; 232: 1859–66.Google Scholar
Link, CD. Invertebrate models of Alzheimer’s disease. Genes Brain Behav 2005; 4: 147–56.CrossRefGoogle ScholarPubMed
Tse, FL, Laplanche, R. Absorption, metabolism, and disposition of [14 C]SDZ ENA 713, an acetylcholinesterase inhibitor, in minipigs following oral, intravenous, and dermal administration. Pharm Res 1998; 15: 1614–20.CrossRefGoogle ScholarPubMed
Wang, D. Tumor necrosis factor-alpha alters electrophysiological properties of rabbit hippocampal neurons. J Alzheimers Dis 2019; 68: 1257–71.CrossRefGoogle Scholar
Brody, DL, Holtzman, DM. Morris water maze search strategy analysis in PDAPP mice before and after experimental traumatic brain injury. Exp Neurol 2006; 197: 330–40.Google Scholar
Li, D, Huang, Y, Cheng, B, et al. Streptozotocin induces mild cognitive impairment at appropriate doses in mice as determined by long-term potentiation and the Morris water maze. J Alzheimers Dis 2016; 54: 8998.Google Scholar
Sadowski, M, Pankiewicz, J, Scholtzova, H, et al. Amyloid-β deposition is associated with decreased hippocampal glucose metabolism and spatial memory impairment in APP/PS1 mice. J Neuropathol Exp Neurol 2004; 63: 418–28.Google Scholar
Xu, H, Rösler, TW, Carlsson, T, et al. Memory deficits correlate with tau and spine pathology in P301S MAPT transgenic mice. Neuropathol Appl Neurobiol 2014; 40: 833–43.CrossRefGoogle ScholarPubMed
Possin, KL, Kramer, JH, Finkbeine, S, et al. Cross-species translation of the Morris maze for Alzheimer’s disease. J Clin Invest 2016; 126: 779–83.CrossRefGoogle ScholarPubMed
Dodart, J-C, Bales, KR, Gannon, KS, et al. Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer’s disease model. Nat Neurosci 2002; 5: 452–7.CrossRefGoogle ScholarPubMed
Shen, L, Hang, B, Geng, Y, et al. Amelioration of cognitive impairments in APPswe/PS1dE9 mice is associated with metabolites alteration induced by total salvianolic acid. PLoS One 2017; 12: e0174763.Google ScholarPubMed
Barbeau, E, Didic, M, Tramoni, E, et al. Evaluation of visual recognition memory in MCI patients. Neurology 2004; 62: 1317–22.Google Scholar
Didic, M, Felician, O, Barbeau, E, et al. Impaired visual recognition memory predicts Alzheimer’s disease in amnestic mild cognitive impairment. Dement Geriatr Cogn Disord 2013; 35: 291–9.CrossRefGoogle ScholarPubMed
Zhang, R, Xue, G, Wang, S, et al. Novel object recognition as a facile behavior test for evaluating drug effects in AβPP/PS1 Alzheimer’s disease mouse model. J Alzheimers Dis 2012; 31: 801–12.CrossRefGoogle ScholarPubMed
Koola, MM. Galantamine–memantine combination in the treatment of Alzheimer’s disease and beyond. Psychiatry Res 2020; 293: 113409.Google Scholar
Wu, Z, Zhao, L, Chen, X, Cheng, X, Zhang, Y. Galantamine attenuates amyloid-β deposition and astrocyte activation in APP/PS1 transgenic mice. Exp Gerontol 2015; 72: 244–50.CrossRefGoogle ScholarPubMed
Puzzo, D, Lee, L, Palmeri, A, Calabrese, G, Arancio, O. Behavioral assays with mouse models of Alzheimer’s disease: practical considerations and guidelines. Biochem Pharmacol 2014; 88: 450–67.Google Scholar
Chen, Y, Shi, G-W, Liang, Z-M, et al. Resveratrol improves cognition and decreases amyloid plaque formation in Tg6799 mice. Mol Med Rep 2019; 19: 3783–90.Google Scholar
Guerreiro, R, Wojtas, A, Bras, J, et al. TREM2 variants in Alzheimer’s disease. N Engl J Med 2013; 368: 117–27.Google Scholar
Lannfelt, L, Relkin, NR, Siemers, ER. Amyloid-ß-directed immunotherapy for Alzheimer’s disease. J Intern Med 2014; 275: 284–95.Google Scholar
De Strooper, B, Vassar, R, Golde, T. The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol 2010; 6: 99107.Google Scholar
Cummings, JL, Morstorf, T, Zhong, K. Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther 2014; 6: 37.Google Scholar
Bales, KR. The value and limitations of transgenic mouse models used in drug discovery for Alzheimer’s disease: an update. Expert Opin Drug Discov 2012; 7: 281–97.Google Scholar
Shineman, DW, Basi, GS, Bizon, JL, et al. Accelerating drug discovery for Alzheimer’s disease: best practices for preclinical animal studies. Alzheimers Res Ther 2011; 3: 28.Google Scholar
Preuss, C, Pandey, R, Piazza, E, et al. A novel systems biology approach to evaluate mouse models of late-onset Alzheimer’s disease. Mol Neurodegener 2020; 15: 67.Google Scholar
Wan, Y-W, Al-Ouran, R, Mangleburg, CG, et al. Meta-analysis of the Alzheimer’s disease human brain transcriptome and functional dissection in mouse models. Cell Reports 2020; 32: 107908.CrossRefGoogle ScholarPubMed
Hayden, KM, Jones, RN, Zimmer, C, et al. Factor structure of the National Alzheimer’s Coordinating Centers uniform dataset neuropsychological battery: an evaluation of invariance between and within groups over time. Alzheimer Dis Assoc Disord 2011; 25: 128–37.Google Scholar
Hansen, DV, Hanson, JE, Sheng, M. Microglia in Alzheimer’s disease. J Cell Biol 2018; 217: 459–72.Google Scholar

Save book to Kindle

To save this book to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×