Baglietto-Vargas D, Forner S, Cai L, Martini AC, Trujillo-Estrada L, Swarup V, Nguyen MM, Do Huynh K, Javonillo DI, Tran KM, Phan J, Jiang S, Kramár EA, Nuñez-Diaz C, Balderrama-Gutierrez G, Garcia F, Childs J, Rodriguez-Ortiz CJ, Garcia-Leon JA, Kitazawa M, Shahnawaz M, Matheos DP, Ma X, Da Cunha C, Walls KC, Ager RR, Soto C, Gutierrez A, Moreno-Gonzalez I, Mortazavi A, Tenner AJ, MacGregor GR, Wood M, Green KN, LaFerla FM. Generation of a humanized Aβ expressing mouse demonstrating aspects of Alzheimer's disease-like pathology. Nat Commun. 2021 Apr 23;12(1):2421. PubMed.
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Hertie Institute for Clinical Brain Research, University of Tübingen, and DZNE Tübingen
Happy birthday, astroglial inclusions!
Thirty years ago, the first APP transgenic mouse model was published claiming that it develops Aβ deposits in the brain (Wirak et al., 1991). Then it turned out that these structures were not Aβ deposits, but rather Periodic acid Schiff-positive (PAS) astrocytic inclusions that occur with aging in some, but not all, aged mouse brains, and which are heavily dependent on the genetic background of the mice. The PAS inclusions are rich in polyglucosan, and they tend to bind nonspecifically to many different antibodies. The paper was corrected, the authors stating that their data no longer support the claim that the Aβ transgene causes the formation of these inclusions in the brain (see comment after Jucker et al., 1992).
Now, 30 years later, this study by Baglietto-Vargas and colleagues finds that the expression of human-sequence Aβ in knock-in mice promotes the appearance of these still-enigmatic lesions. The authors do not cite the 30-year-old paper, and thus I am not sure whether they are aware of the previous work.
I remain skeptical—as I was 30 years ago—that there is a meaningful link between Aβ and these interesting, age-related, glial inclusions. Nevertheless, hopefully the current publication will stimulate the field to work again on the nature and functional consequences of these glial lesions in the aging brain (see also Jucker et al., 1994; Jucker et al., 1994; Mitsuno et al., 1999).
References:
Wirak DO, Bayney R, Ramabhadran TV, Fracasso RP, Hart JT, Hauer PE, Hsiau P, Pekar SK, Scangos GA, Trapp BD. Deposits of amyloid beta protein in the central nervous system of transgenic mice. Science. 1991 Jul 19;253(5017):323-5. PubMed.
Jucker M, Walker LC, Martin LJ, Kitt CA, Kleinman HK, Ingram DK, Price DL. Age-associated inclusions in normal and transgenic mouse brain. Science. 1992 Mar 13;255(5050):1443-5. PubMed.
Jucker M, Walker LC, Schwarb P, Hengemihle J, Kuo H, Snow AD, Bamert F, Ingram DK. Age-related deposition of glia-associated fibrillar material in brains of C57BL/6 mice. Neuroscience. 1994 Jun;60(4):875-89. PubMed.
Jucker M, Walker LC, Kuo H, Tian M, Ingram DK. Age-related fibrillar deposits in brains of C57BL/6 mice. A review of localization, staining characteristics, and strain specificity. Mol Neurobiol. 1994 Aug-Dec;9(1-3):125-33. PubMed.
Mitsuno S, Takahashi M, Gondo T, Hoshii Y, Hanai N, Ishihara T, Yamada M. Immunohistochemical, conventional and immunoelectron microscopical characteristics of periodic acid-Schiff-positive granules in the mouse brain. Acta Neuropathol. 1999 Jul;98(1):31-8. PubMed.
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