Lifeboat Foundation: Safeguarding Humanity
Toggle light / dark theme

Blog

Category: neuroscience – Page 195

Network-based analyses uncover how neuroinflammation-causing microglia in Alzheimer’s disease form

Cleveland Clinic Genome Center researchers have unraveled how immune cells called microglia can transform and drive harmful processes like neuroinflammation in Alzheimer’s disease. The study, published in the journal Alzheimer’s & Dementia, also integrates drug databases with real-world patient data to identify FDA-approved drugs that may be repurposed to target disease-associated microglia in Alzheimer’s disease without affecting the healthy type.

The researchers, led by study corresponding author Feixiong Cheng, Ph.D., hope their unique approach of integrating genetic, chemical and human health data to identify and corresponding drugs will inspire other scientists to take similar approaches in their own research.

Microglia are specialized that patrol our brains, seeking and responding to tissue damage and external threats like bacteria and viruses. Different types of microglial cells use different methods to keep the brain safe. Some may cause neuroinflammation—inflammation in the brain—to fight invaders or kickstart the repair process in damaged cells. Others may work to “eat” dangerous substances in the brain, and clean up damage and debris. However, during Alzheimer’s disease, new types of microglia can form that promote .

Chaperone-mediated autophagy as a modulator of aging and longevity

Chaperone-mediated autophagy (CMA) is the lysosomal degradation of individually selected proteins, independent of vesicle fusion. CMA is a central part of the proteostasis network in vertebrate cells. However, CMA is also a negative regulator of anabolism, and it degrades enzymes required for glycolysis, de novo lipogenesis, and translation at the cytoplasmic ribosome. Recently, CMA has gained attention as a possible modulator of rodent aging. Two mechanistic models have been proposed to explain the relationship between CMA and aging in mice. Both of these models are backed by experimental data, and they are not mutually exclusionary. Model 1, the “Longevity Model,” states that lifespan-extending interventions that decrease signaling through the INS/IGF1 signaling axis also increase CMA, which degrades (and thereby reduces the abundance of) several proteins that negatively regulate vertebrate lifespan, such as MYC, NLRP3, ACLY, and ACSS2. Therefore, enhanced CMA, in early and midlife, is hypothesized to slow the aging process. Model 2, the “Aging Model,” states that changes in lysosomal membrane dynamics with age lead to age-related losses in the essential CMA component LAMP2A, which in turn reduces CMA, contributes to age-related proteostasis collapse, and leads to overaccumulation of proteins that contribute to age-related diseases, such as Alzheimer’s disease, Parkinson’s disease, cancer, atherosclerosis, and sterile inflammation. The objective of this review paper is to comprehensively describe the data in support of both of these explanatory models, and to discuss the strengths and limitations of each.

Chaperone-mediated autophagy (CMA) is a highly selective form of lysosomal proteolysis, where proteins bearing consensus motifs are individually selected for lysosomal degradation (Dice, 1990; Cuervo and Dice, 1996; Cuervo et al., 1997). CMA is mechanistically distinct from macroautophagy and microautophagy, which, along with CMA, are present in most mammalian cells types.

Macroautophagy (Figure 1 A) begins when inclusion membranes (phagophores) engulf large swaths of cytoplasm or organelles, and then seal to form double-membrane autophagosomes. Autophagosomes then fuse with lysosomes, delivering their contents for degradation by lysosomal hydrolases (Galluzzi et al., 2017). Macroautophagy was the first branch of autophagy to be discovered, and it is easily recognized in electron micrograms, based on the morphology of phagophores, autophagosomes, and lysosomes (Galluzzi et al., 2017).

Thalamus degeneration found to impact stroke recovery

A recent study by the Baycrest Centre for Geriatric Care reveals that an area of the brain distinct from the stroke lesion may play a significant role in causing the life-altering symptoms with which survivors are often left, which can include severe challenges with speech, mobility and cognition. These results provide hope that innovative, non-invasive treatments could help improve or even fully reverse post-stroke symptoms.

Strokes (which more than 100,000 Canadians suffer every year) leave behind an area where brain cells have died, called a lesion. However, this cannot explain the widespread consequences of , limiting scientists’ and clinicians’ ability to treat them.

The study, titled “Secondary thalamic dysfunction underlies abnormal large-scale neural dynamics in chronic stroke,” published in the journal Proceedings of the National Academy of Sciences, reveals that degeneration of the thalamus—an area of the brain distinct from the stroke lesion—is a significant contributor to post-stroke symptoms.

Sex differences in neuron protection could reveal Alzheimer’s target

Inhibiting TLR7, an immune signaling protein, may help preserve the protective layer surrounding nerve fibers in the brain during both Alzheimer’s disease and ordinary aging, suggests a study led by researchers at Weill Cornell Medicine. The research is published in the journal Science.

Most in vertebrates are encased in sheaths made largely of myelin, a protein that protects the fibers and greatly enhances the efficiency of their signal conduction. The destruction of myelin sheaths—demyelination—can occur in the context of brain inflammation and can lead to cognitive, movement and other neurological problems. The phenomenon is seen in multiple sclerosis (MS), Alzheimer’s, Parkinson’s and other neurological conditions, as well as in ordinary aging.

Demyelination-linked disorders often show sex differences, and in the study, the researchers looked for underlying mechanisms of demyelination that might help explain these differences. Their experiments in mouse models of Alzheimer’s uncovered TLR7 as a driver of inflammatory demyelination especially in males, but also showed that removing or inhibiting this immune protein can protect against demyelination in both males and females.

Newly Discovered Brain Circuit Predicts Response to Stress

Summary: Researchers identified a brain circuit involving the amygdala and hippocampus that predicts resilience to stress in mice. Mice with disrupted neural communication in this circuit struggled to seek rewards, but activating the neurons restored resilience and improved decision-making.

Using chemogenetics, the team stimulated brain activity in less resilient mice, which then displayed normal behavior and sought sweetened water. This breakthrough suggests potential new, non-invasive treatments for chronic stress and depression in humans, with researchers now exploring similar patterns in human brains.