A large fraction of the public funding devoted to aging research goes towards Alzheimer's disease, a very broad set of initiatives that dovetail with other large investments in mapping and understanding the biochemistry of the brain. This is a diverse area of study, since it involves figuring out how a fair-sized slice of the brain actually works at the detail level in order to understand how it becomes broken in this particular case. This means that a great many papers and research results flow past on a weekly basis. Not all of them are useful; institutions of public funding always turn into jobs programs over time, and that inevitably means a lot of people working on things that are neither useful nor interesting. Further, these sorts of institutions are so risk averse that they essential stop funding true fundamental research, the high-risk search for new knowledge. To have a good shot at winning a grant from the National Institute on Aging you really have to be working on something that is already fairly well known and characterized - grant awarding bodies want to see little risk, and want to pay for an expected outcome. Which is the antithesis of actual research. This is why most of the important work at any given time, the real cutting edge in medical research, is funded by some combination of philanthropy and creative accounting by lab managers.
The nature of government programs is a big problem for any group that seeks to use the public funding mainstream as a guide to what they should be doing to help things move faster in the field. If you simply follow that lead, you wind up like the Ellison Medical Foundation, spending a lot of money on fundamental research to no good end, with very little in the way of practical outcomes to show for it at the end of the day. The National Institute on Aging playbook includes a large amount of waste and make-work, and all too little in the way of earnestly pushing the bounds of the possible. In this day and age, an era of rapid progress in biotechnology and medicine, both pushing the bounds of the possible and practical outcomes should be high on the priority list for aging research, meaning radically better and more effective ways to treat aging and age-related disease. Still, there is a lot of Alzheimer's research underway, and some of it is interesting, potentially useful, or at the very least not make-work. A few recent examples can be found below.
Fibrils, known as amyloids, become intertwined and entangled with each other, causing the so-called 'plaques' that are found in the brains of Alzheimer's patients. Spontaneous formation of the first amyloid fibrils is very slow, and typically takes several decades, which could explain why Alzheimer's is usually a disease that affects people in their old age. However, once the first fibrils are formed, they begin to replicate and spread much more rapidly by themselves, making the disease extremely challenging to control.
Despite its importance, the fundamental mechanism of how protein fibrils can self-replicate without any additional machinery is not well understood. Researchers found that the seemingly complicated process of fibril self-replication is actually governed by a simple physical mechanism: the build-up of healthy proteins on the surface of existing fibrils. The researchers used a molecule known as amyloid-beta, which forms the main component of the amyloid plaques found in the brains of Alzheimer's patients. They found a relationship between the amount of healthy proteins that are deposited onto the existing fibrils, and the rate of the fibril self-replication. In other words, the greater the build-up of proteins on the fibril, the faster it self-replicates. They also showed, as a proof of principle, that by changing how the healthy proteins interact with the surface of fibrils, it is possible to control the fibril self-replication. "This discovery suggests that if we're able to control the build-up of healthy proteins on the fibrils, we might be able to limit the aggregation and spread of plaques."
Two of the key features of Alzheimer's disease are the development of amyloidosis, accumulation of amyloid-ß (Aß) peptides in the brain, and inflammation of the microglia, brain cells that perform immune system functions in the central nervous system. Buildup of Aß into plaques plays a central role in the onset of Alzheimer's, while the severity of neuro-inflammation is believed to influence the rate of cognitive decline from the disease. For this study, researchers administered high doses of broad-spectrum antibiotics to mice over five to six months. At the end of this period, genetic analysis of gut bacteria from the antibiotic-treated mice showed that while the total mass of microbes present was roughly the same as in controls, the diversity of the community changed dramatically. The antibiotic-treated mice also showed more than a two-fold decrease in Aß plaques compared to controls, and a significant elevation in the inflammatory state of microglia in the brain. Levels of important signaling chemicals circulating in the blood were also elevated in the treated mice.
While the mechanisms linking these changes is unclear, the study points to the potential in further research on the gut microbiome's influence on the brain and nervous system. "We don't propose that a long-term course of antibiotics is going to be a treatment - that's just absurd for a whole number of reasons. But what this study does is allow us to explore further, now that we're clearly changing the gut microbial population and have new bugs that are more prevalent in mice with altered amyloid deposition after antibiotics."
Clinically, Alzheimer's disease (AD) is characterized by impairments of memory and cognitive functions. Accumulation of amyloid-β (Aβ) and neurofibrillary tangles are the prominent neuropathologies in patients with AD. Strong evidence indicates that an imbalance between production and degradation of key proteins contributes to the pathogenesis of AD. The mammalian target of rapamycin (mTOR) plays a key role in maintaining protein homeostasis as it regulates both protein synthesis and degradation. A key regulator of mTOR activity is the proline-rich AKT substrate 40 kDa (PRAS40), which directly binds to mTOR and reduces its activity. Notably, AD patients have elevated levels of phosphorylated PRAS40, which correlate with Aβ and tau pathologies as well as cognitive deficits. Physiologically, PRAS40 phosphorylation is regulated by Pim1, a protein kinase of the proto-oncogene family. Here, we tested the effects of a selective Pim1 inhibitor (Pim1i), on spatial reference and working memory and AD-like pathology in 3xTg-AD mice.
We have identified a Pim1i that crosses the blood brain barrier and reduces PRAS40 phosphorylation. Pim1i-treated 3xTg-AD mice performed significantly better than controls. Additionally, 3xTg-AD Pim1i-treated mice showed a reduction in soluble and insoluble Aβ40 and Aβ42 levels, as well as a 45.2% reduction in Aβ42 plaques within the hippocampus. Furthermore, phosphorylated tau immunoreactivity was reduced in the hippocampus of Pim1i-treated 3xTg-AD mice by 38%. Mechanistically, these changes were linked to a significant increase in proteasome activity. These results suggest that reductions in phosphorylated PRAS40 levels via Pim1 inhibition reduce Aβ and Tau pathology and rescue cognitive deficits by increasing proteasome function. Given that Pim1 inhibitors are already being tested in ongoing human clinical trials for cancer, the results presented here may open a new venue of drug discovery for AD by developing more Pim1 inhibitors.
Studying cells from postmortem brains of people who had Alzheimer's disease, researchers previously found that areas of DNA that are typically tightly wound in the cell's nucleus are instead relaxed and unwound in brain cells from Alzheimer's patients. When DNA is unwound it can switch on genes that should be turned off. In the new study, the researchers took a closer look at the nuclei of Alzheimer's patients' brain cells to find out how the DNA becomes unwound. When the researchers used a very high-resolution microscopy technique that let them observe the entire nucleus, they were surprised to see tunnels running through the nucleus of brain cells from people with Alzheimer's disease that were not seen in normal brain cells. "We wanted to find out if these tunnels were actually causing neurons to die or whether they were a side effect of the disease. Using the fly model of Alzheimer's disease we genetically blocked the process of tunnel formation and found that indeed less brain cells died and the flies lived longer. We are now performing lab experiments to see if we can also block the process using drugs."
After identifying this first potential new drug target, the researchers continued their experiments to further elucidate this biological pathway. The cell nucleus is surrounded by what is known as the lamin nucleoskeleton, a structural scaffold made of the protein lamin. They found that when the lamin nucleoskeleton is disrupted and tunnels form, the DNA inside can no longer anchor to the nucleoskeleton and becomes unraveled. In other words, the interaction between tightly wound DNA and the nucleoskeleton is required to maintain the overall 3D architecture of the DNA. They also discovered that the tau that aggregates in the brains of people with Alzheimer's disease disrupts the lamin nucleoskeleton by overstabilizing the actin cytoskeleton found outside of the nucleus, in the cell's cytoplasm. This interrupts the normal coupling between the actin cytoskeleton and the lamin nucleoskeleton, which, in turn, causes the tightly wound DNA to relax. This causes genes to turn on that are not supposed to and, consequently, brain cells die.