Researchers found that the memory loss in Alzheimer's may be reversible. They found a correlation between epigenetic changes and AD, so they targeted the epigenetic enzymes to restore glutamate receptors in mouse brains. Improvements lasted for one week, but they're working on more effective, longer-lasting compounds.

https://medicalxpress.com/news/2019-01-alzheimer-disease-memory-function-preclinical.html

Alzheimer's disease: It may be possible to restore memory function, preclinical study finds

by Ellen Goldbaum, University at Buffalo

January 22, 2019

Research published today in the journal Brain reveals a new approach to Alzheimer's disease (AD) that may eventually make it possible to reverse memory loss, a hallmark of the disease in its late stages.

The team, led by University at Buffalo scientists, found that by focusing on gene changes caused by influences other than DNA sequences—called epigenetics—it was possible to reverse memory decline in an animal model of AD.

"In this paper, we have not only identified the epigenetic factors that contribute to the memory loss, we also found ways to temporarily reverse them in an animal model of AD," said senior author Zhen Yan, Ph.D., a SUNY Distinguished Professor in the Department of Physiology and Biophysics in the Jacobs School of Medicine and Biomedical Sciences at UB.

The research was conducted on mouse models carrying gene mutations for familial AD—where more than one member of a family has the disease—and on post-mortem brain tissues from AD patients.

AD is linked to epigenetic abnormality

AD results from both genetic and environmental risk factors, such as aging, which combine to result in epigenetic changes, leading to gene expression changes, but little is known about how that occurs.

The epigenetic changes in AD happen primarily in the later stages, when patients are unable to retain recently learned information and exhibit the most dramatic cognitive decline, Yan said. A key reason for the cognitive decline is the loss of glutamate receptors, which are critical to learning and short-term memory.

"We found that in Alzheimer's disease, many subunits of glutamate receptors in the frontal cortex are downregulated, disrupting the excitatory signals, which impairs working memory," Yan said.

The researchers found that the loss of glutamate receptors is the result of an epigenetic process known as repressive histone modification, which is elevated in AD. They saw this both in the animal models they studied and in post-mortem tissue of AD patients.

Yan explained that histone modifiers change the structure of chromatin, which controls how genetic material gains access to a cell's transcriptional machinery.

"This AD-linked abnormal histone modification is what represses gene expression, diminishing glutamate receptors, which leads to loss of synaptic function and memory deficits," Yan said.

Potential drug targets

Understanding that process has revealed potential drug targets, she said, since repressive histone modification is controlled or catalyzed by enzymes.

"Our study not only reveals the correlation between epigenetic changes and AD, we also found we can correct the cognitive dysfunction by targeting the epigenetic enzymes to restore glutamate receptors," Yan said.

The AD animals were injected three times with compounds designed to inhibit the enzyme that controls repressive histone modification.

"When we gave the AD animals this enzyme inhibitor, we saw the rescue of cognitive function confirmed through evaluations of recognition memory, spatial memory and working memory. We were quite surprised to see such dramatic cognitive improvement," Yan said.

"At the same time, we saw the recovery of glutamate receptor expression and function in the frontal cortex."

The improvements lasted for one week; future studies will focus on developing compounds that penetrate the brain more effectively and are thus longer-lasting.

Epigenetic advantage

Brain disorders, such as AD, are often polygenetic diseases, Yan explained, where many genes are involved and each gene has a modest impact. An epigenetic approach is advantageous, she said, because epigenetic processes control not just one gene but many genes.

"An epigenetic approach can correct a network of genes, which will collectively restore cells to their normal state and restore the complex brain function," she explained.

"We have provided evidence showing that abnormal epigenetic regulation of glutamate receptor expression and function did contribute to cognitive decline in Alzheimer's disease," Yan concluded. "If many of the dysregulated genes in AD are normalized by targeting specific epigenetic enzymes, it will be possible to restore cognitive function and behavior."

Journal article at: Brain (2019). https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awy354/5298257

New research in skin color genetics found that the variation of light skin among Eurasian people evolved independently from different genetic backgrounds.

https://medicalxpress.com/news/2019-01-genetic-insights-evolution-skin.html

Genetic study provides novel insights into the evolution of skin color

by University College London

January 21, 2019

Skin colour is one of the most visible and variable traits among humans and scientists have always been curious about how this variation evolved. Now, a study of diverse Latin American populations led by UCL geneticists has identified new genetic variations associated with skin colour.

The study, published in the journal Nature Communications, found that the variation of light skin among Eurasian people evolved independently from different genetic backgrounds.

The genetic study analysed pigmentation in over 6,000 Latin Americans, who have a mix of Native American, European and African ancestry.

It is well established that Native Americans are genetically closely related to East Asians, the initial settlement of the Americas occurring some 15-20,000 years ago, through migration from Eastern Siberia into North America. As a consequence, genetic variations in Native Americans are often shared with East Asians.

This study identifies five new associated regions involving skin, eye and hair colour. Genes affecting skin colour in Europeans have been extensively studied, but here researchers identified an important variation in the gene MFSD12 seen uniquely in East Asians and Native Americans.

They show it was under natural selection in East Asians after they split from Europeans around 40,000 years ago, and was then carried over to America by ancient migrations of Native Americans. It is the first time this gene has been linked to skin colour in Native Americans and East Asians.

Dr. Kaustubh Adhikari (UCL Genetics Institute), said: "Our work demonstrates that lighter skin colour evolved independently in Europe and East Asia. We also show that this gene was under strong natural selection in East Asia, possibly as adaptation to changes in sunlight levels and ultraviolet radiation."

Human physical diversity has fascinated biologists for centuries and despite the discovery of hundreds of genes related to such variation, there is still a lot to be understood in order to gain a fuller picture. Scientists have been calling for more diversity in genetics research to ensure that everyone benefits from the medical outcomes of research.

Only recently scientists published the first major study on the genes linked to skin tone diversity in Africa. Latin Americans are similarly underrepresented in genetics research, in particular in pigmentation research.

"It is commonly thought that variation in pigmentation, such as skin colour, in Latin Americans primarily arises due to people's varying degree of European or African ancestry. But our new study shows that there is variation inherited from their Native ancestors as well", said Dr. Javier Mendoza-Revilla (UCL Genetics Institute).

Professor Desmond Tobin (Charles Institute of Dermatology, University College Dublin) explained: "The pigment melanin determines our hair, skin and eye colour. This gene MFSD12 influences how melanin is produced and stored in the skin, thus affecting our skin colour. A darker skin produces more melanin, which can help prevent UV light from damaging our DNA and so offers protection against skin cancer."

"Interestingly, this gene also turned up in the skin colour study in Africans, but the variants were entirely different than those we observe in our study, highlighting the huge genetic diversity in humans and the need to diversify our study populations", emphasized Professor Andres Ruiz-Linares (UCL Genetics Institute), who led the CANDELA project spanning participants from five countries: Brazil, Colombia, Chile, Mexico and Peru.

In addition to skin tone variation, the scientists also noted a wide variation in eye colour among Latin Americans. "Just like skin colour, early research on eye colour was Europe-centric, and mostly focused on the distinction between blue vs. brown eyes. But we show that eye colour is a broad continuum, and by studying the subtler variation within brown to black, we found two new genes linked to it", said Dr. Anood Sohail (University of Cambridge).

The study's findings help explain the variation of skin, hair and eye colour of Latin Americans, shed light on human evolution, and inform an understanding of the genetic risk factors for conditions such as skin cancer.

Journal article:

Kaustubh Adhikari et al, A GWAS in Latin Americans highlights the convergent evolution of lighter skin pigmentation in Eurasia, Nature Communications (2019).

https://www.nature.com/articles/s41467-018-08147-0