Andersen OM, Bøgh N, Landau AM, Pløen GG, Jensen AM, Monti G, Ulhøi BP, Nyengaard JR, Jacobsen KR, Jørgensen MM, Holm IE, Kristensen ML, Alstrup AK, Hansen ES, Teunissen CE, Breidenbach L, Droescher M, Liu Y, Pedersen HS, Callesen H, Luo Y, Bolund L, Brooks DJ, Laustsen C, Small SA, Mikkelsen LF, Sørensen CB. A genetically modified minipig model for Alzheimer's disease with SORL1 haploinsufficiency. Cell Rep Med. 2022 Sep 20;3(9):100740. Epub 2022 Sep 12 PubMed.

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  1. Genetic evidence suggests that truncating SORL1 mutations are causative for AD. Several in vitro models have shown that one consequence of loss of SORL1 function is impairment in endosomal pathways, such as recycling (Hung et al., 2021; Mishra et al., 2022). In this study, Andersen et al. use Gottingen mini-pigs to model SORL1 deficiency in vivo. They used CRISPR/Cas9 to generate SORL1+/- pigs and observed CSF biomarkers that are consistent with both early AD phenotypes and endosomal dysfunction: increases in Aβ and tau, and a reduction in soluble SORLA protein. When mini-pig brains were examined, they found an increase in the size of early endosomes. Swollen early endosomes, indicative of cellular traffic jams, are an early cytopathology in AD and have also been observed in vitro in neuronal models (for example: Knupp et al., 2020). However, the mini-pig brains did not show the classic neuropathologies of AD, amyloid plaques and tau tangles, nor did they show evidence of overt neurodegeneration at the time point analyzed.

    All told, this is a very elegant model that represents presymptomatic conditions driven by SORL1 loss of function, something that is difficult to study in human carriers. This work highlights that biomarkers can reflect early cellular dysfunction and thus identify an early timepoint for potential therapeutic intervention. Furthermore, since endosomal traffic jams have now been observed across multiple SORL1 models, both in vivo and in vitro, this work is further confirmation that the primary driver for SORL1 loss of function leading to AD is through disruptions in the endosomal network.

    This study introduces a powerful preclinical model and future experiments detailing AD-related phenotypes as SORL1-deficient mini-pigs age will be very interesting and informative for the field.

    References:

    Hung C, Tuck E, Stubbs V, van der Lee SJ, Aalfs C, van Spaendonk R, Scheltens P, Hardy J, Holstege H, Livesey FJ. SORL1 deficiency in human excitatory neurons causes APP-dependent defects in the endolysosome-autophagy network. Cell Rep. 2021 Jun 15;35(11):109259. PubMed.

    Mishra S, Knupp A, Szabo MP, Williams CA, Kinoshita C, Hailey DW, Wang Y, Andersen OM, Young JE. The Alzheimer's gene SORL1 is a regulator of endosomal traffic and recycling in human neurons. Cell Mol Life Sci. 2022 Feb 28;79(3):162. PubMed.

    Knupp A, Mishra S, Martinez R, Braggin JE, Szabo M, Kinoshita C, Hailey DW, Small SA, Jayadev S, Young JE. Depletion of the AD Risk Gene SORL1 Selectively Impairs Neuronal Endosomal Traffic Independent of Amyloidogenic APP Processing. Cell Rep. 2020 Jun 2;31(9):107719. PubMed.

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  1. In Mini-Pigs Missing SORL1, Endosomes Swell and Aβ Peptides Rise in CSF