Functional characterization of human neurons in the human-mouse chimeric model for Alzheimer’s disease

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and main cause of dementia among the elderly. It is estimated that about 50 million are affected with dementia worldwide and the prevalence is expected to triple by 2050(1.2). For most of the AD cases (late-onset), 40 susceptibility loci may contribute to the AD according to the genome-wide association studies(3). While for early-onset AD, mutations in genes encoding amyloid precursor protein (APP), presenilin1 (PSEN1) and presenilin 2 (PSEN2) contribute to disease pathology.These mutations have proven important to understand disease mechanisms(4.5).The pathological hallmarks of  AD include the presence of extracellular amyloid-β (Aβ) plaques and intracellular hyperphosphorylated Tau tangles, which are associated with reactive gliosis. The formation and accumulation of toxic amyloid protein is one the earliest detectable pathological changes that occurs several years before the onset of symptoms, and may behave as a trigger to  subsequent pathological progression (6.7) .To explore and evaluate efficient treatments, we are required to study mechanisms at early stages of AD. This implies the need for a good combination of animal models that express all the pathological aspects of AD, as well as reliable in-vivo detection methods.

Our lab has made a breakthrough in creating a novel human-mouse chimeric model, by introducing human pluripotent stem cells (PSCs) derived cortical neuronal precursors into the brain of a APP-PS1 transgenic mice(8). This model has been improved further over the years by using the AppNL-G-F  knock-in mouse model (Balusu S. et al., submitted, 2022). In this human-mouse chimeric model of AD, the genetically normal human neurons, when exposed to Aβ-plaques in vivo, produce all the hallmarks of AD. Thus, it provides us with a novel approach to further explore the pathological changes and responses of the human neurons during the process of amyloid deposition.

Several studies in amyloid mouse models showed early abnormal neuronal activity at initial AD stages both in amyloid mouse models studies and functional magnetic resonance imaging (fMRI) in AD patients(9-11). Our lab recently confirmed the presence of early network hyperactivity related to amyloid pathology in mice and in humans (Shah D., et al, submitted, 2022).

The next step would be to perform a longitudinal in-vivo characterization of these human neurons, and assess how they behave as a response to pathology. A major question that needs to be addressed is whether and how human neurons respond to amyloid pathology differently than mouse neurons. For this purpose, calcium imaging approaches which require to express a calcium indicator (GCaMP) are widely used to measure cell activity in-vivo(12.13). To correctly position before calcium imaging, magnetic resonance imaging (MRI) with contrast agents, especially super paramagnetic iron oxide nanoparticles (SPIOs), need to be used in tracking cells in vivo(14).

 In this project, we aim to optimize MRI methods to track grafted human neurons and define their exact positions after injection in an APP knock-in mouse model. Next, we aim to perform longitudinal functional characterization of human neurons and assess their response to Aβ pathology with calcium imaging. Finally, we aim to study the response of human neurons to treatment with anti-amyloid antibodies and assess whether human and mouse cells respond to these therapies differently.

References:1. PMID: 30497964. 2.Prince, M. et al. World Alzheimer Report 2015.  3. PMID 30820047. 4. PMID: 27016693. 5. PMID: 23142261. 6. PMID: 25988462. 7. PMID: 35177833. 8. PMID: 28238547. 9. PMID: 22592800, 10. PMID: 28459436. 11. PMID: 29986165;12. PMID: 28362436; 13. PMID: 31080068.14. PMID:32792506