A core problem in several dementias is the inability to form new memories and gradual loss of old memories. Funded by a ZonMW open competition grant, the teams of Wiep Scheper (Amsterdam UMC Human Genetics/FGA), Priyanka Rao-Ruiz (VU MCN) and Michel van den Oever (VU MCN) will collaborate to obtain mechanistic insight into memory formation and persistence and how this is disturbed in dementia.
The majority of dementias, including Alzheimer’s disease, are “tauopathies”, characterized by the aggregation of tau protein. Although tau pathology is considered to be a causal factor resulting in symptoms like memory loss, it is unknown how tau aggregation induces memory impairment. Accumulating evidence shows that formation and retrieval of a specific memory is controlled by small populations of neurons: engram cells. The exact molecular pathways underlying memory processing are largely unknown, but several studies point to a critical role of the integrated stress response (ISR) in memory processing. The ISR is dysregulated in neurons with tau pathology, which is likely to interfere with memory processing.
The Van den Oever lab (engram cell-tagging and -intervention), the Rao Ruiz lab (proteomics of engram cells) and the Scheper lab (tau pathology, ISR and proteostasis) will combine their expertise and state-of-the-art technologies, including virus-based tagging of engram cells with tau pathology and inducible dysregulation of the ISR in combination with engram-cell specific proteomics and targeted intervention approaches. Through this synergistic and multidisciplinary CNCR collaboration, they aim to obtain detailed insight into how tau pathology disrupts engram cells, thereby contributing to a better understanding of dementia, a major socio-economic challenge.
