Marisa Vanheusden, Innovation Scientist at Muna Therapeutics, discussed the company’s latest efforts in novel drug target discovery and drug development in the context of neurodegenerative diseases. She focused on Muna’s MiND-Map platform which makes use of spatial transcriptomics for drug target identification directly from post-mortem human brains in the context of neurodegenerative diseases.
Within their pipeline, Alzheimer’s disease is their most advanced cohort studied with the MiND-Map platform. Alzheimer’s is puzzling because there is a large elderly patient population that has a substantial amount of amyloid plaque within their brains but they remain cognitively intact. Therefore, this raises questions as to whether there are resilient mechanisms at work in the brain that prevent people from experiencing neurodegeneration.
Some may argue that these patients will eventually develop neurodegeneration, but they just haven’t yet. However, Vanheusden explained that there are individuals called centenarians that are over 100 years old and have a significant amount of plaque load within their brains, but remain cognitively healthy for decades and eventually die without developing neurodegeneration. This argues in favour of the idea that resilient mechanisms are in play.
Understanding the cellular environment surrounding these amyloid plaques and what induces a protective cellular response or a malignant one towards these amyloid plaques. So, understanding the cellular interactions could shine a light on new drug targets to create more resilience within elderly brains to prevent neurodegenerative diseases like Alzheimer’s.
To test these hypotheses, Vanheusden conducted a proof of concept study which involved applying spatial transcriptomics to uncover cellular responses around these amyloid plaques in APP NLGF mice. 57 plaque-induced genes (PIGs) were uncovered that highlighted pathways that are strongly co-regulated around these plaques. These pathways may function together to resolve amyloid stress.
To corroborate these cellular responses in humans, the team collected samples from different patient cohorts, including healthy controls, resilient individuals with amyloid plaques but no cognitive decline, Alzheimer's patients, and centenarians. 10X Visium was used to spatially profile the cohorts.
The analysis revealed that while plaque loads were similar across the different groups, P Tau burden, particularly neuritic plaques, was significantly higher in Alzheimer’s patients, especially in cortical layer 5. This outcome supports the idea that P Tau pathology is more closely associated with neurodegeneration.
A key finding was the identification of a “greenyellow” gene module enriched in microglial markers and inflammatory pathways, including TREM2: a known Alzheimer’s risk gene. This module responded to both amyloid and P Tau pathology and overlapped with plaque-induced genes previously identified in mouse models.
Further analysis showed that different subsets of genes within this module were associated with early plaque response or later Tau pathology and that inflammatory glial subtypes were the primary drivers of these responses. Overall, the MiND-Map platform thus enables a human-centric, spatially resolved approach to uncovering the cellular and molecular underpinnings of Alzheimer’s disease.
