Today the topic is protein aggregation in the aging brain, its consequences, and efforts to both understand and remove these aggregates. I’d noticed a few interesting research notices in the past few weeks, but they were pushed into the backlog by other matters. They are generally representative of the interest in aggregates in the research community, and of the incremental progress towards practical treatments. Removing solid deposits of misfolded or otherwise altered proteins from the brain has proven to be far more challenging than was first hoped when immunotherapies aimed at clearing the amyloid-β associated with Alzheimer’s disease began earnest development more than a decade ago. There are signs of progress, and a broadening of different approaches, but it is hard to say when success will arrive in the clinic. Many of the current approaches are clearly very incremental, and even if realized as medical technologies would only produce marginal improvements.
Alzheimer’s disease is where the bulk of funding goes in this part of the field, but it is only one of a score of age-related medical conditions that appear to be driven by the buildup of harmful proteins in the central nervous system. If the occasional post on the molecular biochemistry of neurodegenerative conditions here at Fight Aging! interests you, then you should consider adding ALZFORUM to your news feed. It is a good example of what can be achieved in advocacy and education if given sufficient funding. The breadth of mainstream interest in tackling Alzheimer’s disease has supplied sufficient resources to fill in all of the areas of a research community, including an education and awareness arm, not just the bare bones.
Arguably this large research community should be viewed not as an effort to produce cures, but as an effort to understand the biochemistry and operation of the brain. The prospect of therapies for neurodegeneration is the rallying flag, the promised application of new knowledge that generates necessary public support. The real goal is knowledge, not treatments. At the large scale, all fields of science work this way: the pure aim of increased knowledge is funded by whatever that knowledge can be used to achieve. Absent advocacy to generate public appreciation of clear, near-future applications, it is very challenging to obtain the funding needed to perform any sort of medical research. Yet medical research is so clearly the greatest determinant of our future health and longevity that I have to see this state of affairs as an important failing of human nature. Important matters never seem to gain the focus that they merit.
Researchers have found cell receptors abnormally overexpressed in post-mortem brains of those with Parkinson’s and Alzheimer’s diseases, and that they can be inhibited in animal models to clear toxic protein buildup, reduce brain inflammation, and improve cognitive performance. These dual findings mark the first time that the receptors, discoindin domain receptors (DDRs), have been understood to play a role in Parkinson’s and Alzheimer’s diseases. They are primarily known as potential targets against cancer. “Activation of these cell receptors appear to prevent brain cells from cleaning out the trash – the toxic buildup of proteins, such as alpha-synuclein, tau and amyloid, common in neurodegenerative diseases.”
When DDRs are over-expressed, their actions become destructive. One reason may be that DDRs are protein enzymes known as tyrosine kinases that act as on and off switches of the cell self-cleaning process known as autophagy. Excess DDRs activation may switch off autophagy, resulting in build-up of toxic proteins inside brain cells and possibly breakdown of the blood-brain barrier, common in neurodegenerative diseases. DDRs inhibition with a tyrosine kinase inhibitor appears to insulate the brain via blood-brain barrier repair, which prevents harmful immune cells that circulate in the body from getting into the brain where they can indiscriminately attack and kill healthy and sick neurons, like those that have been unable to perform autophagy. “We studied an experimental tyrosine kinase inhibitor that enters the brain and inhibits DDRs. Inhibition of these receptors with a low dose of the agent, LCB-03-110, or reduction of DDRs expression in several models of Parkinson’s and Alzheimer’s disease, allows nerve cells to switch on autophagy to clear toxic proteins and help the brain insulate itself from circulating inflammatory cells. This led to cognitive improvement in our animal models.”
New research shows that the APP gene variant protecting against Alzheimer’s disease significantly decreases plasma beta-amyloid levels in a population cohort. This is a significant discovery, as many on-going drug trials in the field of Alzheimer’s disease focus on decreasing beta-amyloid levels in the brain tissue. According to the study, the APP A673T gene variant, which is a variant in the amyloid precursor protein gene protecting against Alzheimer’s disease, leads to an average of 30 per cent decreased levels of the beta-amyloid subtypes 40 and 42. The effects of this previously discovered gene variant were analysed by utilising data from the METSIM (METabolic Syndrome In Men) study.
Approximately 0.3% of the population are carriers of the APP A673T gene variant. Although the variant itself is rare, the observed association with decreased plasma beta-amyloid levels is important from the viewpoint of Alzheimer’s drug trials. Several on-going drug trials for Alzheimer’s disease focus on decreasing beta-amyloid levels in the brain tissue. The findings from the population cohort in eastern Finland show that a life-long decrease in beta-amyloid levels is not associated with detrimental effects on lipid or glucose metabolism, or on any other metabolically relevant events.
Scientists have identified a couple of crucial steps in the formation of a protein called amyloid beta, which accumulates in clumps, or “plaques,” in the brains of people with Alzheimer’s disease. Those discoveries inspired efforts at disrupting the biochemical carving of amyloid beta’s precursor protein into its final, toxic shape. The latest drugs being tested try to silence an enzyme, called BACE1, that cuts the precursor protein. But BACE1 has other functions that are beneficial, so stopping it altogether could bring unwanted side effects – including disrupting the production of myelin, the protective insulation of brain cells. Researchers have found that changing where the cut is made – in effect, guiding the enzyme’s scissors to a different point – could achieve the same goal, with less collateral damage.
Researchers built upon two discoveries in the past decade of two rare mutations: one, found in Italian people, that leads to early onset Alzheimer’s disease, and another, found in Icelandic people, that staves off Alzheimer’s disease. The team was particularly intrigued by the diametrically opposite effects of both mutations because they affected the same point on the precursor protein’s chain of 770 amino acids, swapping one acid for another. The researchers injected one set of mice with a virus carrying the Italian gene mutation, and another set with the Icelandic mutation. They found that the amino acid substitution affected where the precursor protein was cleaved. The Icelandic mutation resulted in a shortened form of amyloid beta, which does not become “sticky” and turn into plaque. The Italian mutation produced a longer, “stickier” version of amyloid beta, which ultimately becomes neuron-smothering plaque. Actually, the effects were a matter of degree: Each mutation led to more cuts in one location or more cuts in the other location. But in the gradual degradation of Alzheimer’s disease, that could be enough – reducing the levels of the offending toxin could translate into many more years of life before cognitive decline sets in.