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The few established causal genes in Alzheimer's disease (AD), mutations in APP and PSENs, have been functionally characterized using biomarkers, capturing an in vivo profile reflecting the disease's initial preclinical phase. SORL1, a gene encoding the endosome recycling receptor SORLA, epidemiologically behaves as a causal gene when truncating mutations lead to partial loss of protein function. Here, in an effort to test whether SORL1 can indeed function as an AD causal gene, we used CRISPR-Cas9-based gene editing to develop a novel model of SORL1 haploinsufficiency in Goettingen Minipigs taking advantage of porcine models for biomarker investigations. SORL1 haploinsufficiency in young minipigs was found to phenocopy the preclinical in vivo profile of AD observed with other causal genes, resulting in spinal fluid abnormalities in Aβ and tau, with no evident neurodegeneration or amyloid plaque formation. These studies provide functional support that SORL1 is a bona fide causal gene in AD, and when taken together with recent insight on other AD-causal genes, support the idea that dysfunctional endosomal recycling is a dominant pathogenic pathway in the disease.

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Background Recent preclinical and clinical studies have shed light on the possible impact of sex and oestrous/menstrual cycle on ketamine’s antidepressant action but with incongruous results. The preclinical studies that have shown the effects of ovarian sex hormones have not done so in animal models of depression. Thus, the aim of the present study is to scrutinize the acute behavioural responses to a subanaesthetic dose of S-ketamine in males vs females and in different oestrous phases in free-cycling females in a well-powered translational approach. Methods We evaluated the behavioural sensitivity to 20 mg/kg S-ketamine (i.p.) in male and female Flinders sensitive line (FSL) rats and their counterpart Flinders resistant line (FRL) rats subjected to the open field and forced swim tests. Female rats were disaggregated into different oestrous phases, and the behavioural outcomes were compared. Results Acute administration of S-ketamine had robust antidepressant-like effects in FSL rats. Within our study power, we could not detect sex- or oestrous-cycle-specific different antidepressant-like responses to S-ketamine in FSLs. Fluctuations in the levels of ovarian sex hormones across different oestrous cycles did not behaviourally affect the S-ketamine’s rapid-acting antidepressant mode of action. No sex- or oestrous-cycle-related impact on behavioural despair was observed even among FRLs and saline-treated FSLs. Conclusions We conclude that physiological oscillations of estrogen and progesterone levels neither amplify nor diminish the behavioural antidepressant-like effect of S-ketamine. In addition, fluctuations of ovarian sex hormones do not predispose female animals to exhibit enhanced or reduced depressive- and anxiety-like behaviours.

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