Research

Individuals with Down syndrome bear important similarities to patients with Alzheimer’s disease (AD), including excessive levels of beta-amyloid proteins because the amyloid precursor protein gene resides on chromosome 21. As individuals with Down syndrome age, they have a greatly increased risk (nearly six times more) of developing a type of dementia that’s either the same as, or very similar to, Alzheimer’s disease.

In the new center, Co-Director Li-Huei Tsai will strive to learn whether an innovative, non-invasive potential AD treatment her lab has developed could help people with DS. Called GENUS for “Gamma ENtrainment Using Sensory stimuli” the method uses lights that flicker and sound that buzzes at the frequency of 40 Hz to stimulate 40 Hz gamma rhythms in the brain. In experiments with several different mouse models of AD, the technique reduces AD pathology and improves learning and memory, in part by activating the brain’s vasculature and its inherent immune cells, microglia, to clear out the harmful proteins amyloid and tau.

Core Collaborator Ed Boyden, who has worked with Tsai in developing GENUS, will bring two other novel technologies from his lab to the center’s work. A technique called “Temporal Interference,” which he developed in collaboration with Tsai, can stimulate brain activity by precisely projecting interfering electric fields from electrodes on the scalp into targeted brain regions. Where the signals interfere, they stimulate neural electrical frequencies, potentially improving brain functions such as cognition or memory.

Meanwhile, to help better understand DS at every scale in the brain, he hopes to contribute a technique called “Expansion Microscopy” in which he can chemically expand out all the biomolecules in a cell or tissue, effectively making both individual neurons and the circuits in which they function much larger and therefore easier to see and study in unprecedented detail.

In this area of research center researchers are working to understand the complex cellular and genomic influences underlying Down syndrome and to leverage these results toward potential treatment options for the benefit of people with the condition. Research will build on and greatly extend the successful MIT outcomes of projects sponsored by the Alana Foundation from 2015–2018.

With a $1.7 million gift to MIT in 2015, Alana funded studies in the Tsai lab to create new laboratory models of Down syndrome and to improve understanding of the mechanisms of the disorder and potential therapies.

Since then Senior Fellow Hiruy Meharena has been building an understanding of how trisomy 21 affects the different cell types of the brain — not only the different types of neurons but also microglia, astrocytes and oligodendrocytes — and how their altered interactions affect brain function. In the lab, Meharena does this by utilizing mosaic DS human cells that are genetically identical except that they differ by the extra copy of chromosome 21. They can then be studied alone or together in systems called cerebral organoids. Within individual cells, he’s been able to track how the specific arrangement of chromosomes in the nucleus differs when there is a third copy of chromosome 21, and how that re-arrangement affects gene expression. One of his key findings is that the impact on gene expression, although different in each cell type, is genome-wide, rather than limited to the extra chromosome.

Core Collaborator Manolis Kellis’ work uses advanced computational approaches to help explain the complex question of how genomic differences lead to differences in health and cognitive functions. By systematically profiling single-cell differences in gene expression levels and in epigenomic signatures, he is bridging the gap between genetic variation and disease, and pinpointing promising genes and cell types to guide therapeutic interventions. In collaboration with Tsai on AD, for instance, Kellis’ computational analyses revealed distinct changes in several cell types. This help elucidate diverse pathways with putative causal roles, the cell types where they likely act, whether they occur early or late during AD, and how they differ by gender. His team is collaborating with Tsai’s to perturb the elucidated pathways to prevent and even reverse AD symptoms in human cells and mice.