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Do reelin- and somatostatin-positive neurons protect against dementia?

Alzheimer's disease is associated with an accumulation of amyloid protein in the brain. These clump-like plaques lead to neurodegeneration and memory impairment. Interestingly, however, not everyone who is cognitively impaired in old age has amyloid plaques in their brain and, conversely, not everyone with plaques develops Alzheimer's dementia. Why is this the case?

In a paper recently published in the journal Cell, neurobiologist Hansruedi Mathys from the University of Pittsburgh School of Medicine, neuroscientist Li-Huei Tsai and computer scientist Manolis Kellis from the Massachusetts Institute of Technology in Cambridge have now attempted to shed light on this question. They had access to data from a large study (ROSMAP), in the course of which the cognitive and motor skills of thousands of people were tracked over many years.

The researchers took tissue samples from 427 brains of deceased study participants for a precise analysis of the nerve cells in the cerebral cortex. Some of the subjects had developed dementia, which is typical of advanced Alzheimer's disease, some had only mild cognitive impairment and the rest showed no signs of impairment. The analysis included a total of around 2.3 million cell nuclei from the prefrontal cortex, which is responsible for higher brain functions. In order to classify the corresponding nerve cells, the researchers sequenced all active genes and thus created a molecular atlas of the brain. This allows genetic changes and signaling pathways associated with dementia and Alzheimer's resilience to be uncovered.

The present work demonstrated a coordinated increase in the so-called cohesin complex, which holds sister chromatids together, and a cellular response to DNA damage in neurons and oligodendrocytes of Alzheimer's patients. In fact, excitatory neurons showed increased gene fusions, which indicate chromosomal structural variations and can lead to neurodegeneration.

The authors also identified two cell types that carry a marker that is apparently lost during severe cognitive impairment. One encodes reelin, a protein associated with schizophrenia, and the other somatostatin, a neuropeptide that functions as a hormone in the body. The number of cells with these two markers remained high in cognitively healthy subjects, even when large amounts of amyloid plaques were detectable in their brains. Both are inhibitory nerve cells that interrupt neuronal communication. Apparently, reelin- or somatostatin-positive interneurons are particularly susceptible in Alzheimer's disease and die prematurely. Interestingly, a reelin mutation was recently detected in a man with high amyloid levels who did not develop dementia.

Finally, several genes involved in FGF signaling were identified in the present work. FGF1 and FGF22 correlate positively with global cognitive function and, similar to FGF17 discussed earlier in this blog, may have a positive effect on memory.


Mathys H, Peng Z, Boix CA, ..., Tsai L-H (2023) Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer's disease pathology. Cell 186:4365-4385

Image credit: iStock/koto_feja


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