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

Objective subtle cognitive difficulties predict amyloid accumulation and neurodegeneration

December 31, 2019

Science Daily/University of California - San Diego

Writing in the December 30, 2019 online issue of Neurology, researchers at University of California San Diego School of Medicine and Veterans Affairs San Diego Healthcare System report that accumulating amyloid -- an abnormal protein linked to neurodegenerative conditions such as Alzheimer's disease (AD) -- occurred faster among persons deemed to have "objectively-defined subtle cognitive difficulties" (Obj-SCD) than among persons considered to be "cognitively normal."

Classification of Obj-SCD, which has been previously shown to predict progression to mild cognitive impairment (MCI) and dementia, is determined using non-invasive but sensitive neuropsychological measures, including measures of how efficiently someone learns and retains new information or makes certain types of errors.

The new findings, say authors, suggest that Obj-SCD can be detected during the preclinical state of AD when amyloid plaques are accumulating in the brain, neurodegeneration is just starting, but symptoms of impairment on total scores on thinking and memory tests have not yet been recorded.

"The scientific community has long thought that amyloid drives the neurodegeneration and cognitive impairment associated with Alzheimer's disease," said senior author Mark W. Bondi, PhD, professor of psychiatry at UC San Diego School of Medicine and the VA San Diego Healthcare System. "These findings, in addition to other work in our lab, suggest that this is likely not the case for everyone and that sensitive neuropsychological measurement strategies capture subtle cognitive changes much earlier in the disease process than previously thought possible.

"This work, led by Dr. Kelsey Thomas, has important implications for research on treatment targets for AD, as it suggests that cognitive changes may be occurring before significant levels of amyloid have accumulated. It seems like we may need to focus on treatment targets of pathologies other than amyloid, such as tau, that are more highly associated with the thinking and memory difficulties that impact people's lives."

Study participants were enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI), an on-going effort (launched in 2003) to test whether regular, repeated brain imaging, combined with other biological markers and clinical assessments, can measure the progression of MCI and early AD. Seven hundred and forty-seven persons were involved in this study: 305 deemed cognitively normal, 153 with Obj-SCD and 289 MCI. All underwent neuropsychological testing and both PET and MRI scans.

The research team found that amyloid accumulation was faster in persons classified with Obj-SCD than in the cognitively normal group. Those classified as Obj-SCD also experienced selective thinning of the entorhinal cortex, a region of the brain impacted very early in Alzheimer's disease and associated with memory, navigation and perception of time. Persons with MCI had more amyloid in their brain at the start of the study, but they did not have faster accumulation of amyloid compared to those with normal cognition. However, those with MCI had more widespread temporal lobe atrophy, including the hippocampus.

Broadly speaking, scientists believe that for most people, AD is likely caused by a combination of genetic, lifestyle and environmental factors. Increasing age is a primary, known risk factor. The amyloid hypothesis or amyloid cascade model posits that accumulating amyloid protein plaques in the brain kill neurons and gradually impair specific cognitive functions, such as memory, resulting in AD dementia. However, many scientists are now questioning the amyloid hypothesis given the large number of clinical trials in which drugs targeted and successfully cleared amyloid from the brain but did not impact the trajectory of cognitive decline.

The ability to identify those at risk for AD before significant impairment and before or during the phase of faster amyloid accumulation would be a clinical boon, said authors, providing both a way to monitor disease progression and a window of opportunity to apply potential preventive or treatment strategies.

Currently, both approaches are limited. Some risk factors for Alzheimer's can be minimized, such as not smoking, managing vascular risk factors such as hypertension or following a healthy diet with regular exercise. There are a handful of medications approved for treating symptoms of AD, but as yet, there is no cure.

"While the emergence of biomarkers of Alzheimer's disease has revolutionized research and our understanding of how the disease progresses, many of these biomarkers continue to be highly expensive, inaccessible for clinical use or not available to those with certain medical conditions," said first author Thomas, PhD, assistant professor of psychiatry at UC San Diego School of Medicine and research health scientist at the VA San Diego Healthcare System.

"A method of identifying individuals at risk for progression to AD using neuropsychological measures has the potential to improve early detection in those who may otherwise not be eligible for more expensive or invasive screening."

https://www.sciencedaily.com/releases/2019/12/191231111811.htm

Indications why older people are more susceptible to Alzheimer's disease

July 8, 2019

Science Daily/DZNE - German Center for Neurodegenerative Diseases

The risk of developing Alzheimer's disease increases with age. Susanne Wegmann of the German Center for Neurodegenerative Diseases (DZNE) in Berlin and colleagues have uncovered a possible cause for this connection: Certain molecules involved in the disease, termed tau-proteins, spread more easily in the aging brain. This has been determined in laboratory experiments. The current study was carried out in close collaboration with researchers in the US at Harvard Medical School and Massachusetts General Hospital. The results were recently published in the journal Science Advances.

Alzheimer's disease usually begins with memory decline and later affects other cognitive abilities. Two different kinds of protein deposits in the patient's brain are involved in the disease: "Amyloid beta plaques" and "tau neurofibrillary tangles." The emergence of tau neurofibrillary tangles reflects disease progression: they first manifest in the brain's memory centers and then appear in other areas in the course of the disease. Tau proteins or tau aggregates probably migrate along nerve fibers and thereby contribute to the spreading of the disease throughout the brain.

Tau spreads more rapidly in aging brains

What is the role of aging in tau propagation? If the protein spread more easily in older brains, this could explain the increased susceptibility of older people to Alzheimer's disease. Wegmann and her colleagues tested this hypothesis.

Using a "gene vector" -- a tailored virus particle -- the scientists channeled the blueprint of the human tau protein into the brains of mice. Individual cells then began to produce the protein. Twelve weeks later, the researchers examined how far the tau protein had travelled from the production site. "Human tau proteins spread about twice as fast in older mice as compared to younger animals," Wegmann summarized the results.

The experimental part of the study was carried out in the laboratory of Bradley Hyman at Harvard Medical School in Boston, USA, where Susanne Wegmann worked for several years. In 2018, she moved to the DZNE's Berlin site, where her research group addresses various questions on tau-related disease mechanisms. Here, the major part of data analysis and summarizing the results took place.

Healthy and pathological tau

The experimental setting also allowed the scientists to analyze tau propagation in more detail. The protein exists in a healthy, soluble form in every neuron of the brain. However, in Alzheimer's disease, it can change its shape and convert into a pathological form prone to aggregate into fibrils. "It has long been thought that it is primarily the pathological form of tau that passes from one cell to the next. However, our results show that the healthy version of the protein also propagates in the brain and that this process increases in old age. Cells could also be harmed by receiving and accumulating large amounts of healthy tau," said Wegmann.

The findings from the study raise a number of questions that Wegmann will now tackle with her research group at the DZNE: Which processes underlie the increased spreading of tau in the aging brain? Is too much tau protein produced or too little defective protein removed? Answering these questions may open up new therapeutic options in the long term.

https://www.sciencedaily.com/releases/2019/07/190708135940.htm