Transgenic Amyloid Precursor Protein Mouse Models of Amyloidosis. Incomplete Models for Alzheimer's Disease but Effective Predictors of Anti-amyloid Therapies

Overview

Journal Alzheimers Dement

Specialties Neurology
Psychiatry

Date 2023 Dec 12

PMID 38085800

Authors

David G Morgan

Bruce T Lamb

Affiliations

Soon will be listed here.

Abstract

Introduction: Amyloid precursor protein (APP) transgenic mice are models of Alzheimer's disease (AD) amyloidosis, not all of AD. Diffuse, compacted, and vascular deposits in APP mice mimic those found in AD cases.

Methods: Most interventional studies in APP mice start treatment early in the process of amyloid deposition, consistent with a prevention treatment regimen. Most clinical trials treat patients with established amyloid deposits in a therapeutic treatment regimen.

Results: The first treatment to reduce amyloid and cognitive impairment in mice was immunotherapy. The APP mouse models not only predicted efficacy, but presaged the vascular leakage called ARIA. The recent immunotherapy clinical trials that removed amyloid and slowed cognitive decline confirms the utility of these early APP models when used in therapeutic designs.

Discussion: New mouse models of AD pathologies will add to the research armamentarium, but the early models have accurately predicted responses to amyloid therapies in humans.

Citing Articles

Transgenic amyloid precursor protein mouse models of amyloidosis. Incomplete models for Alzheimer's disease but effective predictors of anti-amyloid therapies.

Morgan D, Lamb B Alzheimers Dement. 2023; 20(2):1459-1464.

PMID: 38085800 PMC: 10916971. DOI: 10.1002/alz.13566.

References

Chang W, Huang X, Downs D, Cirrito J, Koelsch G, Holtzman D . Beta-secretase inhibitor GRL-8234 rescues age-related cognitive decline in APP transgenic mice. FASEB J. 2010; 25(2):775-84. PMC: 3023390. DOI: 10.1096/fj.10-167213. View

Chishti M, Yang D, Janus C, Phinney A, Horne P, Pearson J . Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. J Biol Chem. 2001; 276(24):21562-70. DOI: 10.1074/jbc.M100710200. View

Calderon-Garciduenas A, Duyckaerts C . Alzheimer disease. Handb Clin Neurol. 2017; 145:325-337. DOI: 10.1016/B978-0-12-802395-2.00023-7. View

Lemere C, Maron R, Spooner E, Grenfell T, Mori C, Desai R . Nasal A beta treatment induces anti-A beta antibody production and decreases cerebral amyloid burden in PD-APP mice. Ann N Y Acad Sci. 2001; 920:328-31. DOI: 10.1111/j.1749-6632.2000.tb06943.x. View

Janus C, Pearson J, McLaurin J, Mathews P, Jiang Y, Schmidt S . A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature. 2001; 408(6815):979-82. DOI: 10.1038/35050110. View

Jack Jr C, Bennett D, Blennow K, Carrillo M, Dunn B, Budd Haeberlein S . NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018; 14(4):535-562. PMC: 5958625. DOI: 10.1016/j.jalz.2018.02.018. View

Duyckaerts C, Delatour B, Potier M . Classification and basic pathology of Alzheimer disease. Acta Neuropathol. 2009; 118(1):5-36. DOI: 10.1007/s00401-009-0532-1. View

Mucke L, Masliah E, Yu G, Mallory M, Rockenstein E, Tatsuno G . High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci. 2000; 20(11):4050-8. PMC: 6772621. View

Rockenstein E, Mallory M, Mante M, Sisk A, Masliaha E . Early formation of mature amyloid-beta protein deposits in a mutant APP transgenic model depends on levels of Abeta(1-42). J Neurosci Res. 2001; 66(4):573-82. DOI: 10.1002/jnr.1247. View

10.

Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T . Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999; 400(6740):173-7. DOI: 10.1038/22124. View

11.

Asher S, Priefer R . Alzheimer's disease failed clinical trials. Life Sci. 2022; 306:120861. DOI: 10.1016/j.lfs.2022.120861. View

12.

Li Y, Schindler S, Bollinger J, Ovod V, Mawuenyega K, Weiner M . Validation of Plasma Amyloid-β 42/40 for Detecting Alzheimer Disease Amyloid Plaques. Neurology. 2021; 98(7):e688-e699. PMC: 8865895. DOI: 10.1212/WNL.0000000000013211. View

13.

Wilcock D, Rojiani A, Rosenthal A, Subbarao S, Freeman M, Gordon M . Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. J Neuroinflammation. 2004; 1(1):24. PMC: 539292. DOI: 10.1186/1742-2094-1-24. View

14.

Brendel M, Jaworska A, Overhoff F, Blume T, Probst F, Gildehaus F . Efficacy of chronic BACE1 inhibition in PS2APP mice depends on the regional Aβ deposition rate and plaque burden at treatment initiation. Theranostics. 2018; 8(18):4957-4968. PMC: 6217065. DOI: 10.7150/thno.27868. View

15.

Jacobsen H, Ozmen L, Caruso A, Narquizian R, Hilpert H, Jacobsen B . Combined treatment with a BACE inhibitor and anti-Aβ antibody gantenerumab enhances amyloid reduction in APPLondon mice. J Neurosci. 2014; 34(35):11621-30. PMC: 4145168. DOI: 10.1523/JNEUROSCI.1405-14.2014. View

16.

Fukumoto H, Takahashi H, Tarui N, Matsui J, Tomita T, Hirode M . A noncompetitive BACE1 inhibitor TAK-070 ameliorates Abeta pathology and behavioral deficits in a mouse model of Alzheimer's disease. J Neurosci. 2010; 30(33):11157-66. PMC: 6633483. DOI: 10.1523/JNEUROSCI.2884-10.2010. View

17.

Robakis N, Ramakrishna N, Wolfe G, Wisniewski H . Molecular cloning and characterization of a cDNA encoding the cerebrovascular and the neuritic plaque amyloid peptides. Proc Natl Acad Sci U S A. 1987; 84(12):4190-4. PMC: 305050. DOI: 10.1073/pnas.84.12.4190. View

18.

Lamb B, Call L, Slunt H, Bardel K, Lawler A, Eckman C . Altered metabolism of familial Alzheimer's disease-linked amyloid precursor protein variants in yeast artificial chromosome transgenic mice. Hum Mol Genet. 1997; 6(9):1535-41. DOI: 10.1093/hmg/6.9.1535. View

19.

Hort J, Andel R, Mokrisova I, Gazova I, Amlerova J, Valis M . Effect of donepezil in Alzheimer disease can be measured by a computerized human analog of the Morris water maze. Neurodegener Dis. 2013; 13(2-3):192-6. DOI: 10.1159/000355517. View

20.

McDade E, Voytyuk I, Aisen P, Bateman R, Carrillo M, De Strooper B . The case for low-level BACE1 inhibition for the prevention of Alzheimer disease. Nat Rev Neurol. 2021; 17(11):703-714. DOI: 10.1038/s41582-021-00545-1. View