The first step in understanding a disease is identifying its causes. In the case of Alzheimer’s disease (AD), this has been challenging as the disease manifests differently and progresses at different rates between individuals. Although the genetic mutations associated with familial Alzheimer’s disease were discovered decades ago, there are still no effective therapies for patients suffering from this debilitating condition.

The search for commonalities among Alzheimer’s patients has led to the identification of two proteins that are consistently found in the brains of those with the disease: amyloid beta and tau. Amyloid beta is found in plaques that accumulate outside of neuron cells, while tau is found in tangles that form inside neurons.

The Amyloid Precursor Protein (APP) has been identified as a gene that can play a role in the development of both amyloid plaques and tau tangles. Therefore, several transgenic mouse models have been generated to overexpress human APP. These AD mouse models have several drawbacks as a result of the random integration of the transgene into the genome, including non-physiological protein levels and ectopic expression. Many of these limitations have been addressed using knock-in approaches to target mutations into the mouse APP gene.

The In Vivo Translational Sciences group at Denali Therapeutics, led by Dr Pascal E. Sanchez, was striving to generate a mouse model of amyloid pathology that will be made widely available to the scientific community. Dr Sanchez and his colleague Dr Dan Xia contacted Ozgene to develop a novel APP knock-in mouse model to knock three disease-causing coding mutations (Swedish, Arctic and Austrian) to the mouse APP gene using homologous recombination. Additionally, three amino acids APP G676R, APP F681Y and APP R684H were substituted to humanize the mouse Aβ_1-42 region.

The resulting AppSAA knock-in mouse model displays AD-like pathophysiology including amyloid beta pathology, neurodegeneration, brain metabolism, glial responses and behavioural phenotypes characterized. These mice recapitulate some features of Alzheimer’s, including a progressive accumulation of amyloid plaques and vascular amyloid deposits, altered astroglial and microglial responses and elevation of neurodegeneration biomarkers.

The Denali studies of this model reveal that fibrillar amyloid beta in microglia is associated with lipid dyshomeostasis consistent with lysosomal dysfunction and foam cell phenotypes as well as profound immuno-metabolic perturbations. These new insights pave the way for further investigations into metabolic pathways in microglia responding to Alzheimer’s pathogenesis. Denali Therapeutics, in collaboration with the Jackson Laboratory, has made this mouse model available to the scientific community in the hope that it will serve as a valuable resource to investigate AD pathophysiology as well as potential therapies for this debilitating disease.

Mol Neurodegener. 2022 Jun 11;17(1):41. doi: 10.1186/s13024-022-00547-7.
Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia
Dan Xia, Steve Lianoglou, Thomas Sandmann, Meredith Calvert, Jung H Suh, Elliot Thomsen, Jason Dugas, Michelle E Pizzo, Sarah L DeVos, Timothy K Earr, Chia-Ching Lin, Sonnet Davis, Connie Ha, Amy Wing-Sze Leung, Hoang Nguyen, Roni Chau, Ernie Yulyaningsih, Isabel Lopez, Hilda Solanoy, Shababa T Masoud, Chun-Chi Liang, Karin Lin, Giuseppe Astarita, Nathalie Khoury, Joy Yu Zuchero, Robert G Thorne, Kevin Shen, Stephanie Miller, Jorge J Palop, Dylan Garceau, Michael Sasner, Jennifer D Whitesell, Julie A Harris, Selina Hummel, Johannes Gnörich, Karin Wind, Lea Kunze, Artem Zatcepin, Matthias Brendel, Michael Willem, Christian Haass, Daniel Barnett, Till S Zimmer, Anna G Orr, Kimberly Scearce-Levie, Joseph W Lewcock, Gilbert Di Paolo, Pascal E Sanchez.

bioRxiv. 2021 Jan 19. doi: https://doi.org/10.1101/2021.01.19.426731
Fibrillar Aβ causes profound microglial metabolic perturbations in a novel APP knock-in mouse model
Dan Xia, Steve Lianoglou, Thomas Sandmann, Meredith Calvert, Jung H. Suh, Elliot Thomsen, Jason Dugas, Michelle E. Pizzo, Sarah L. DeVos, Timothy K. Earr, Chia-Ching Lin, Sonnet Davis, Connie Ha, Hoang Nguyen, Roni Chau, Ernie Yulyaningsih, Hilda Solanoy, Shababa T. Masoud, Richard Liang, Karin Lin, Robert G. Thorne, Dylan Garceau, Jennifer D. Whitesell, Michael Sasner, Julie A. Harris, Kimberly Scearce-Levie, Joseph W. Lewcock, Gilbert Di Paolo, Pascal E. Sanchez.

Further research articles related to the App locus and Alzheimer’s Disease featuring Ozgene mouse models

PLoS Biol. 2021 Sep 14;19(9):e3001358. doi: 10.1371/journal.pbio.3001358. eCollection 2021 Sep.
Synthesis of human amyloid restricted to liver results in an Alzheimer disease-like neurodegenerative phenotype
Virginie Lam, Ryusuke Takechi, Mark J Hackett, Roslyn Francis, Michael Bynevelt, Liesl M Celliers, Michael Nesbit, Somayra Mamsa, Frank Arfuso, Sukanya Das, Frank Koentgen, Maree Hagan, Lincoln Codd, Kirsty Richardson, Brenton O’Mara, Rainer K Scharli, Laurence Morandeau, Jonathan Gauntlett, Christopher Leatherday, Jan Boucek, John C L Mamo

Nat Med 2015 Aug 17. doi: 10.1038/nm.3924.
APP intracellular domain-WAVE1 pathway reduces amyloid-β production
Ilaria Ceglia, Christiane Reitz, Jodi Gresack, Jung-Hyuck Ahn, Victor Bustos, Marina Bleck, Xiaozhu Zhang, Grant Martin, Sanford M Simon, Angus C Nairn, Paul Greengard, Yong Kim

J Mol Neurosci 2004;24(1):23
Novel approaches to models of Alzheimer’s disease pathology for drug screening and development
Laura Shaughnessy, Beth Chamblin, Lori McMahon, Ayyappan Nair, Mary Beth Thomas, John Wakefield, Frank Koentgen, Ram Ramabhadran