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                                                          4. Changes in synapses related to protein 43 (GAP-43) speed up the spread of tau in Alzheimer’s disease
                                                          News | 12/02/2024 | Research Spotlight

                                                          Changes in synapses related to protein 43 (GAP-43) speed up the spread of tau in Alzheimer’s disease

                                                          A combined neuroimaging and biofluid biomarker study investigated whether synaptic changes are associated with accelerated tau spreading in Alzheimer’s disease (AD). They found that higher levels of the presynaptic protein GAP-43 speed up the spread of tau in AD. These findings are relevant for developing treatments to slow down the progression of the disease. 
                                                           Research Spotlight: Photo of the researcher and a quote about the impact of the research

                                                          This is a summary of Franzmeier, N., Dehsarvi, A., Steward, A. et al. Elevated CSF GAP-43 is associated with accelerated tau accumulation and spread in Alzheimer’s disease. Which appeared in Nature Communications 15, 202 (2024). https://doi.org/10.1038/s41467-023-44374-w


                                                          The challenge

                                                          In Alzheimer’s disease (AD), the accumulation of the protein amyloid-beta (Aβ) is assumed to initiate a cascade of pathological processes, including the spread of tau proteins, which trigger neurodegeneration and cognitive decline. Earlier studies suggest that synaptic connections between neurons are key pathways for the spreading of tau. Higher synaptic activity and connectivity are associated with accelerated tau secretion at the synapse and a faster trans-synaptic tau spread. Aβ plaques lead to synaptic changes, resulting in increased levels of the growth-associated protein GAP-43 – a protein that plays a key role in axonal growth and the formation of new synaptic connections. We aimed to investigate whether higher levels of GAP-43 detectable in the cerebrospinal fluid, as a marker for changes in synaptic activity, contribute to the trans-synaptic spread of tau in Alzheimer patients – a hypothesis that had not been systematically tested in AD patients yet.


                                                          Our approach

                                                          We conducted a study involving 93 patients, covering the AD spectrum from cognitively normal to dementia, as well as a control group without AD pathology. Each participant underwent an amyloid-PET scan to determine the initial levels of amyloid in the brain and a lumbar puncture to determine the GAP-43 protein levels in the cerebrospinal fluid. To track the accumulation and spread of tau over time, participants underwent PET scans over a period of approximately three years. To better understand how tau spreads, we used functional MRI scans of healthy individuals to create a model of the brain’s connectome along which we modeled tau spread.


                                                          Our findings

                                                          We found that higher baseline CSF GAP-43 levels are associated with accelerated Aβ-related tau accumulation. Furthermore, we found that higher CSF GAP-43 levels specifically increase the Aβ-related spread of tau pathology from local epicenters in which tau emerges first across functionally connected brain regions.


                                                          The implications

                                                          Our research helps better understand how Aβ and synaptic changes may conjointly drive tau aggregation and spread, which ultimately triggers neurodegeneration and the development of dementia symptoms. The importance of synapses in the spread of tau suggests that synaptic changes could be key targets for preventing tau spread in Alzheimer’s disease.


                                                          Creating SyNergies

                                                          This study was a collaboration of 2 of our AIs (Nicolai Franzmeier and Matthias Brendel) and colleagues from the University of Gothenburg (Kaj Blennow, Henrik Zetterberg, and Michael Schöll). 

                                                          Participating Universities
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                                                          SyNergy is funded by the Deutsche Forschungsgemeinschaft (German Research Foundation) within the framework of the German Excellence Strategy (EXC 2145 SyNergy – ID 390857198). The Excellence Strategy promotes outstanding research at German universities. 

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                                                          Munich Cluster for Systems Neurology (SyNergy)

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