Prion protein recruits its neuronal receptor NCAM to lipid rafts to activate p59fyn and to enhance neurite outgrowth

In spite of advances in understanding the role of the cellular prion protein (PrP) in neural cell interactions, the mechanisms of PrP function remain poorly characterized. We show that PrP interacts directly with the neural cell adhesion molecule (NCAM) and associates with NCAM at the neuronal cell surface. Both cis and trans interactions between NCAM at the neuronal surface and PrP promote recruitment of NCAM to lipid rafts and thereby regulate activation of fyn kinase, an enzyme involved in NCAM-mediated signaling. Cis and trans interactions between NCAM and PrP promote neurite outgrowth. When these interactions are disrupted in NCAM-deficient and PrP-deficient neurons or by PrP antibodies, NCAM/PrP-dependent neurite outgrowth is arrested, indicating that PrP is involved in nervous system development cooperating with NCAM as a signaling receptor

Sex and gender considerations in Alzheimer’s disease: The Women’s Brain Project contribution

The global population is expected to have about 131.5 million people living with Alzheimer’s disease (AD) and other dementias by 2050, posing a severe health crisis. Dementia is a progressive neurodegenerative condition that gradually impairs physical and cognitive functions. Dementia has a variety of causes, symptoms, and heterogeneity concerning the influence of sex on prevalence, risk factors, and outcomes. The proportion of male-to-female prevalence varies based on the type of dementia. Despite some types of dementia being more common in men, women have a greater lifetime risk of developing dementia. AD is the most common form of dementia in which approximately two-thirds of the affected persons are women. Profound sex and gender differences in physiology and pharmacokinetic and pharmacodynamic interactions have increasingly been identified. As a result, new approaches to dementia diagnosis, care, and patient journeys should be considered. In the heart of a rapidly aging worldwide population, the Women’s Brain Project (WBP) was born from the necessity to address the sex and gender gap in AD. WBP is now a well-established international non-profit organization with a global multidisciplinary team of experts studying sex and gender determinants in the brain and mental health. WBP works with different stakeholders worldwide to help change perceptions and reduce sex biases in clinical and preclinical research and policy frameworks. With its strong female leadership, WBP is an example of the importance of female professionals’ work in the field of dementia research. WBP-led peer-reviewed papers, articles, books, lectures, and various initiatives in the policy and advocacy space have profoundly impacted the community and driven global discussion. WBP is now in the initial phases of establishing the world’s first Sex and Gender Precision Medicine Institute. This review highlights the contributions of the WBP team to the field of AD. This review aims to increase awareness of potentially important aspects of basic science, clinical outcomes, digital health, policy framework and provide the research community with potential challenges and research suggestions to leverage sex and gender differences. Finally, at the end of the review, we briefly touch upon our progress and contribution toward sex and gender inclusion beyond Alzheimer’s disease

Sex and gender differences and biases in artificial intelligence for biomedicine and healthcare

Precision Medicine implies a deep understanding of inter-individual differences in health and disease that are due to genetic and environmental factors. To acquire such understanding there is a need for the implementation of different types of technologies based on artificial intelligence (AI) that enable the identification of biomedically relevant patterns, facilitating progress towards individually tailored preventative and therapeutic interventions. Despite the significant scientific advances achieved so far, most of the currently used biomedical AI technologies do not account for bias detection. Furthermore, the design of the majority of algorithms ignore the sex and gender dimension and its contribution to health and disease differences among individuals. Failure in accounting for these differences will generate sub-optimal results and produce mistakes as well as discriminatory outcomes. In this review we examine the current sex and gender gaps in a subset of biomedical technologies used in relation to Precision Medicine. In addition, we provide recommendations to optimize their utilization to improve the global health and disease landscape and decrease inequalities.This work is written on behalf of the Women’s Brain Project (WBP) (www.womensbrainproject.com/), an international organization advocating for women’s brain and mental health through scientific research, debate and public engagement. The authors would like to gratefully acknowledge Maria Teresa Ferretti and Nicoletta Iacobacci (WBP) for the scientific advice and insightful discussions; Roberto Confalonieri (Alpha Health) for reviewing the manuscript; the Bioinfo4Women programme of Barcelona Supercomputing Center (BSC) for the support. This work has been supported by the Spanish Government (SEV 2015–0493) and grant PT17/0009/0001, of the Acción Estratégica en Salud 2013–2016 of the Programa Estatal de Investigación Orientada a los Retos de la Sociedad, funded by the Instituto de Salud Carlos III (ISCIII) and European Regional Development Fund (ERDF). EG has received funding from the Innovative Medicines Initiative 2 (IMI2) Joint Undertaking under grant agreement No 116030 (TransQST), which is supported by the European Union’s Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA).Peer ReviewedPostprint (published version

Fishing for Prion Protein Function

The prion protein is infamous for its role in devastating neurological diseases, but its normal, physiological function has remained mysterious. A new study uses the experimentally tractable zebrafish model to obtain fresh clues to this puzzle

Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis

The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for Alzheimer’s disease (AD). The influence of apoE on amyloid β (Aβ) accumulation may be the major mechanism by which apoE affects AD. ApoE interacts with Aβ and facilitates Aβ fibrillogenesis in vitro. In addition, apoE is one of the protein components in plaques. We hypothesized that certain anti-apoE antibodies, similar to certain anti-Aβ antibodies, may have antiamyloidogenic effects by binding to apoE in the plaques and activating microglia-mediated amyloid clearance. To test this hypothesis, we developed several monoclonal anti-apoE antibodies. Among them, we administered HJ6.3 antibody intraperitoneally to 4-mo-old male APPswe/PS1ΔE9 mice weekly for 14 wk. HJ6.3 dramatically decreased amyloid deposition by 60–80% and significantly reduced insoluble Aβ40 and Aβ42 levels. Short-term treatment with HJ6.3 resulted in strong changes in microglial responses around Aβ plaques. Collectively, these results suggest that anti-apoE immunization may represent a novel AD therapeutic strategy and that other proteins involved in Aβ binding and aggregation might also be a target for immunotherapy. Our data also have important broader implications for other amyloidosis. Immunotherapy to proteins tightly associated with misfolded proteins might open up a new treatment option for many protein misfolding diseases

Characterization of prion protein function by focal neurite stimulation

The cellular prion protein (PrPC), encoded by the PRNP gene, is a ubiquitous glycoprotein, which is highly expressed in the brain. This protein, mainly known for its role in neurodegenerative diseases, is involved in several physiological processes including neurite outgrowth. By using a novel focal stimulation technique, we explored the potential function of PrPC, in its soluble form, as a signaling molecule. Thus, soluble recombinant prion proteins (recPrP) encapsulated in micro-vesicles were released by photolysis near the hippocampal growth cones. Local stimulation of wild-type growth cones with full-length recPrP induced neurite outgrowth and rapid growth cone turning towards the source. This effect was shown to be concentration dependent. Notably, PrPC-knockout growth cones were insensitive to recPrP stimulation, but this property was rescued in PrPknockout growth cones expressing GFP-PrP. Taken together, our findings indicate that recPrP functions as a signaling molecule, and that its homophilic interaction with membrane-anchored PrPC might promote neurite outgrowth and facilitate growth cone guidance. \ua9 2016. Published by The Company of Biologists Ltd

The N Terminus of the Prion Protein Mediates Functional Interactions with the Neuronal Cell Adhesion Molecule (NCAM) Fibronectin Domain

The cellular form of the prion protein (PrPC) is a highly conserved glycoprotein mostly expressed in the central and peripheral nervous systems by different cell types in mammals. A misfolded, pathogenic isoform, denoted as prion, is related to a class of neurodegenerative diseases known as transmissible spongiform encephalopathy. PrPC function has not been unequivocally clarified, and it is rather defined as a pleiotropic protein likely acting as a dynamic cell surface scaffolding protein for the assembly of different signaling modules. Among the variety of PrPC protein interactors, the neuronal cell adhesion molecule (NCAM) has been studied in vivo, but the structural basis of this functional interaction is still a matter of debate. Here we focused on the structural determinants responsible for human PrPC (HuPrP) and NCAM interaction using stimulated emission depletion (STED) nanoscopy, SPR, and NMR spectroscopy approaches. PrPC co-localizes with NCAM in mouse hippocampal neurons, and this interaction is mainly mediated by the intrinsically disordered PrPC N-terminal tail, which binds with high affinity to the NCAM fibronectin type-3 domain. NMR structural investigations revealed surface-interacting epitopes governing the interaction between HuPrP N terminus and the second module of the NCAM fibronectin type-3 domain. Our data provided molecular details about the interaction between HuPrP and the NCAM fibronectin domain, and revealed a new role of PrPC N terminus as a dynamic and functional element responsible for protein-protein interaction