AGING

The Human Brain Makes an Evolutionary Jump

Study Reveals Possible Barrier to Developing Rodent Model of Alzheimer’s

It comes as no surprise that for particular functions, what goes on in a mouse brain may be very different from what goes on in a human brain. According to new research from the lab of HMS professor of pathology Bruce Yankner, the human and mouse brains have evolutionarily diverged to the point where certain fundamentals of the aging process are diametrically opposed. The discovery sheds light on why researchers have not yet successfully modeled neurodegenerative conditions like Alzheimer’s disease in a mouse.

“This is the first study that has surveyed the entire genome for genes that are expressed in the young and aging brain from mouse to man,” said Yankner, who is also a professor of neurology at Children’s Hospital Boston.
The findings appeared online Oct. 2 in PLoS One.

Repressing Networks
In June 2004, Yankner and colleagues described in the journal Nature a cluster of genes in the human brain whose activity decreased with age. Among the roughly 11,000 genes that they targeted, they found that four percent of these genes decreased in individuals aged 40 and up. Many of these genes, interestingly, were involved with learning and memory and play important roles in communication between neurons.

But these findings begged a key question: To what extent is this phenomenon conserved? If mammalian brains are fairly similar, as is commonly assumed, is this age-related gene repression shared by our closest relatives?

To delve more deeply into this question, Yankner and graduate student Patrick Loerch, along with HMS instructor in pathology Tao Lu, who was first author on the 2004 paper, compared genomewide age-related gene expression changes in the cortex of humans with brain changes in mice, using rhesus macaque data as a control. To do this, the researchers looked at pathologically characterized brain samples from all different age groups, isolating RNA. They cross-referenced the data with the Allen Brain Atlas, a comprehensive online database containing genetic information on the mouse brain. They also conducted microarray analyses of isolated human neural cell types in culture to validate data from the online atlas.

The team found that in many cases gene processes were conserved (such as the upregulation of the neuroprotective gene apolipoprotein D and downregulation of the synaptic cAMP signaling gene calcium/calmodulin-dependent protein kinase IV). However, the group found that this was not the case for a large group of age-related neuronal genes involved in synaptic activity. In particular, genes related to the family of GABA receptors, a group of proteins that dampen the activity of neighboring neurons, fared differently in humans compared with mice. While this cluster of molecules appeared unaffected in the aging brain of rodents, in humans and to a lesser extent in rhesus, this same group experienced a highly significant loss of activity.

The authors conclude that the loss of activity of these particular genes in higher primates as opposed to rodents indicates that this feature of the aging brain has evolved relatively recently.

Elucidating Alzheimer’s
The singling out of this particular group of genes may be significant, since their primary function is to inhibit large groups of downstream neuronal genes involved in learning and memory. Yankner hypothesizes that this sort of systematic neuronal repression facilitates a brain function that may be more precise and focused. But when these GABA-associated genes lose their ability to repress large networks of subsequent genes, Yankner believes, this may account for overactivation of some brain regions known to occur with aging. The tight reins that have channeled an efficient neuronal processing are loosened, and more genes—and neurons—get to work, but without a greater coherence or effectiveness.

“This has been observed in functional brain scans,” said Yankner. “It’s known that if you give an aged person a task that requires planning and foresight, a greater portion of the executive part of the brain will become activated compared with young people. In a young person, a very discreet part of the brain is activated, indicative of efficient function. Most older people activate a larger area and invoke more of the brain, and there is evidence that this is compensatory to get the job done, even though the brain is working less efficiently. It’s not understood why. These findings may offer a clue to this.”

The findings may also offer clues to some of the basic mechanisms of Alzheimer’s disease.

Alzheimer’s and other neurodegenerative diseases are unique to humans. While researchers have created mouse models whose brains form the amyloid deposits typically associated with neurodegeneration, they have yet to develop an animal model that exhibits many of the degenerative features of Alzheimer’s, Parkinson’s, or related conditions. This fundamental genetic difference in how the brain ages may explain why this is the case.

In addition, the loss of this inhibitory system in humans predisposes neurons to being overstimulated, which in turn may increase the potential for excitotoxicty, a condition in which the neurotransmitter glutamate becomes overactive and begins to damage the nervous system. Excitotoxicity is suspected by many of being a feature of Alzheimer’s disease (reinforced by the fact that one of the only effective Alzheimer’s drugs, memantine, binds to the glutamate receptor that causes excitotoxicity). Compared with humans, mice may not be as vulnerable to excitotoxicity as they age.

“The assumption has always been that if you understand the mouse brain you understand the human brain, and to an extent, you do,” said Yankner. “But ultimately, until someone figures out a way to genetically replicate this age-dependent process of neuronal repression in an animal model, we’ll need to keep studying the human brain as well as mouse models.”

—David Cameron

Conflict Disclosure: The authors declare no conflicts of interest.

Funding Sources: The National Institute on Aging

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