Pillar 2: SynSAD

Successful treatment of Alzheimer’s disease (AD) relies on early interventions that delay or prevent clinical symptoms before significant neurodegeneration occurs. While current therapies primarily focus on reducing amyloid plaque burden, their impact on cognitive decline remains limited. Synaptic dysfunction represents one of the earliest characteristics of AD, directly driving neuronal network imbalance and cognitive impairment. Recent cerebrospinal fluid (CSF) proteomics findings identified a distinct synaptic subtype of AD encompassing both sporadic and familial cases, driven by combined neuronal and glial dysfunction.

Pillar 2 aims to characterize the molecular and cell physiological mechanisms underlying early synaptic impairments in this synaptic AD subtype. Specifically, the project focuses on synapses with hypothesized selective vulnerability, including hippocampal excitatory synapses onto vulnerable interneurons and connections between memory-encoding engram cells. Additional objectives include determining the role of AMPA receptor subunit composition in synaptic vulnerability, evaluating the involvement of astrocytes and microglia in selective synapse pruning, and testing targeted cognitive, pharmacological, and genetic interventions.

Using APP/PS1 transgenic mice and human induced pluripotent stem cell (iPSC)-derived familial AD models (including neuron-glia co-cultures), Pillar 2 integrates molecular, physiological, and behavioral approaches. Cell-type and synapse-specific transcriptomic and proteomic profiling will establish the molecular determinants of synaptic vulnerability. Functional, genetic, and pharmacological manipulations will subsequently determine causal relationships between specific molecular targets, synaptic integrity, and cognitive performance.

This research will provide critical mechanistic insights into early synaptic breakdown in AD, delineate selectively vulnerable synapse subpopulations, and validate neuron-glia targets. Ultimately, these findings will advance the development of novel, subtype-specific therapeutic strategies targeting the earliest stages of Alzheimer's disease.

Who is involved?

Pillar 2 is led by prof. Paul Lucassen (UvA) and prof. Ronald van Kesteren

(VU), as they work together with Harm Krugers (UvA), Aniko Korosi (UvA), Helmut Kessels (UvA), en Priyanka Rao Ruiz (VU). They will all supervise PhD students, postdocs, and other (non-)scientific staff.

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