CoEN5025 NANOSYN: Unravelling synaptic pathology in Alzheimer's disease and Dementia with Lewy bodies using super-resolution microscopy

Alzheimer's disease (AD) and Dementia with Lewy bodies (DLB) are the two most common causes of dementia. In order to find effective treatments, it is critical that we understand the exact causes. Accumulation of Abeta and tau proteins in the brain occurs early in people with AD. In DLB, a protein called alpha-synuclein accumulates early inside neurons. We know that synapses, the most critical structures for communication between neurons, are lost very early in these diseases. However, the precise mechanism by which these proteins damage synapses is poorly understood due to the lack of adequate techniques. Here, we will apply the most advanced tools available to investigate the presence of abnormal proteins at synapses in a unique set of human brain samples. We will also investigate the effects of toxic proteins on synapse composition. This information will be invaluable for the development of more specific treatments for the two most common causes of dementia.

Alzheimer's disease (AD) and Dementia with Lewy bodies (DLB) are the two most common causes of dementia, characterized by neuronal loss and abnormal protein aggregates. In AD, the pathological hallmarks are extracellular aggregates of amyloid beta (Ab) and intracellular aggregates of hyperphosphorylated tau (ptau). In DLB, the hallmark is aggregated alpha-synuclein (alpha-syn) in the neuronal soma and processes. Synapse loss is an early and key feature in both diseases. However, the characterization of synaptic damage in humans has remained elusive due to the lack of sensitive techniques to resolve these small structures. In this project, we will apply 2 super-resolution microscopy techniques (Array Tomography [AT] and Single-Molecule Localization super-resolution Microscopy [SMLM] approaches, such as STORM and DNA-PAINT) to systematically investigate synaptic damage in single synapses in 5 human brain regions affected by AD and DLB pathology. We will use a unique collection of human brain samples collected in Edinburgh and Barcelona ready for AT/SMLM. We will compare the localization of oligomeric and fibrillar forms of Ab, ptau and alpha-syn at millions of synapses across several brain regions. This project will apply the latest technology to unravel this key phenomenon and could lead to the development of more specific treatments aimed at restoring synapses in these common dementias.