What happens around an Alzheimer plaque?

July 22, 2020

Science Daily/VIB (the Flanders Institute for Biotechnology)

The brains of people living with Alzheimer's are riddled with plaques: protein aggregates consisting mainly of amyloid beta. Despite decades of research, the real contribution of these plaques to the disease process is still not clear. A research team led by Bart De Strooper and Mark Fiers at the VIB-KU Leuven Center for Brain & Disease Research in Leuven, Belgium used pioneering technologies to study in detail what happens in brain cells in the direct vicinity of plaques. Their findings, published in the prestigious journal Cell, show how different cell types in the brain work together to mount a complex response to amyloid plaques which is likely protective at first, but later on damaging to the brain.

The role of amyloid plaques in Alzheimer's disease has puzzled scientists ever since Alois Alzheimer first described them in the brain of a woman with young onset dementia. Now, over a century later, we have learned a lot about the molecular processes that lead to neurodegeneration and subsequent memory loss, but the relationship between the plaques and the disease process in the brain is still ambiguous.

"Amyloid plaques might act as a trigger or as a driver of disease, and the accumulation of amyloid beta in the brain likely initiates a complex multicellular neurodegenerative process," says professor Bart De Strooper (VIB-KU Leuven). His team set out to map the molecular changes that take place in cells near amyloid plaques.

"We used the latest technologies to analyze genome-wide transcriptomic changes induced by amyloid plaques in hundreds of small tissue domains," explains Mark Fiers, co-lead on the study. "In this way, we could generate a large data set of transcriptional changes that occur in response to increasing amyloid pathology, both in mouse and human brains."

Two co-expression networks

"We focused on the transcriptomic changes in the immediate neighborhood of the amyloid plaques, with a 50 micrometer perimeter," explains Wei-Ting Chen, a postdoc in De Strooper's team. In a well-studied genetic mouse model showing amyloid pathology, the scientists identified two novel gene co-expression networks that appeared highly sensitive to amyloid beta deposition.

Chen: "With increasing amyloid beta deposition, a multicellular co-expressed gene response was established encompassing no less than 57 plaque-induced genes." These genes were mainly expressed in astroglia and microglia, two types of supportive brain cells, and were not co-expressed in the absence of amyloid plaques.

"We also found interesting alterations in a second network, expressed mainly by another type of cells, namely oligodendrocytes," adds Ashley Lu, PhD student in the team. "This gene network was activated under mild amyloid stress but depleted in microenvironments with high amyloid accumulation."

"Many of the genes in both networks show similar alterations in human brain samples, strengthening our observations," adds Fiers.

Targeting plaques

"Our data demonstrate that amyloid plaques are not innocent bystanders of the disease, as has been sometimes suggested, but in fact induce a strong and coordinated response of all surrounding cell types," says De Strooper.

"Further work is needed to understand whether, and when, removal of amyloid plaques -- for instance by antibody therapy currently in development to treat amyloid plaques -- is sufficient to reverse these ongoing cellular processes."

Whether antibody binding to amyloid plaques could also modulate these glial responses remains to be determined. "It would in any case complicate the interpretation of the outcome of clinical trials as these cellular effects might be different between different antibodies," adds De Strooper.

https://www.sciencedaily.com/releases/2020/07/200722134916.htm

Creation of new brain cells plays an underappreciated role in Alzheimer's disease

August 30, 2019

Science Daily/University of Chicago

Researchers show how in genetic forms of Alzheimer's, a process called neurogenesis, or the creation of new brain cells, can be disrupted by the brain's own immune cells.

Much of the research on the underlying causes of Alzheimer's disease focuses on amyloid beta (Aß), a protein that accumulates in the brain as the disease progresses. Excess Aß proteins form clumps or "plaques" that disrupt communication between brain cells and trigger inflammation, eventually leading to widespread loss of neurons and brain tissue.

Aß plaques will continue to be a major focus for Alzheimer's researchers. However, new work by neuroscientists at the University of Chicago looks at another process that plays an underappreciated role in the progression of the disease.

In a new study published in the Journal of Neuroscience, Sangram Sisodia, PhD, the Thomas Reynolds Sr. Family Professor of Neurosciences at UChicago, and his colleagues show how in genetic forms of Alzheimer's, a process called neurogenesis, or the creation of new brain cells, can be disrupted by the brain's own immune cells.

Some types of early onset, hereditary Alzheimer's are caused by mutations in two genes called presenilin 1 (PS1) and presenilin 2 (PS2). Previous research has shown that when healthy mice are placed into an "enriched" environment where they can exercise, play and interact with each other, they have a huge increase in new brain cells being created in the hippocampus, part of the brain that is important for memory. But when mice carrying mutations to PS1 and PS2 are placed in an enriched environment, they don't show the same increase in new brain cells. They also start to show signs of anxiety, a symptom often reported by people with early onset Alzheimer's.

This led Sisodia to think that something besides genetics had a role to play. He suspected that the process of neurogenesis in mice both with and without Alzheimer's mutations could also be influenced by other cells that interact with the newly forming brain cells.

Focus on the microglia

The researchers focused on microglia, a kind of immune cell in the brain that usually repairs synapses, destroys dying cells and clears out excess Aß proteins. When the researchers gave the mice a drug that causes microglial cells to die, neurogenesis returned to normal. The mice with presenilin mutations were then placed into an enriched environment and they were fine; they didn't show any memory deficits or signs of anxiety, and they were creating the normal, expected number of new neurons.

"It's the most astounding result to me," Sisodia said. "Once you wipe out the microglia, all these deficits that you see in these mice with the mutations are completely restored. You get rid of one cell type, and everything is back to normal."

Sisodia thinks the microglia could be overplaying their immune system role in this case. Alzheimer's disease normally causes inflammation in the microglia, so when they encounter newly formed brain cells with presenilin mutations they may overreact and kill them off prematurely. He feels that this discovery about the microglia's role opens another important avenue toward understanding the biology of Alzheimer's disease.

"I've been studying amyloid for 30 years, but there's something else going on here, and the role of neurogenesis is really underappreciated," he said. "This is another way to understand the biology of these genes that we know significantly affect the progression of disease and loss of memory."

https://www.sciencedaily.com/releases/2019/08/190830112832.htm