Imagine you have a recipe for a cake that calls for two different ingredients: flour and sugar. You might think that the more flour and sugar you add, the better the cake will turn out. But what if I told you that the amount of flour and sugar didn’t actually make a difference in how tasty the cake was? That’s essentially what scientists discovered when studying a rat model of Alzheimer’s disease. They found that while levels of a protein called Aβ, which is associated with Alzheimer’s pathology, were increased in both male and female rats with a genetic mutation, it was the magnitude of long-term potentiation (LTP) – a process important for learning and memory – that correlated with behavioral performance. In other words, it wasn’t the amount of Aβ that affected how well the rats performed on cognitive tasks, but rather how well their brains were able to establish and maintain synaptic connections. This finding challenges the traditional view that Aβ accumulation is the main driver of Alzheimer’s disease and suggests that targeting pathways involved in LTP dysfunction may be a more effective strategy for treatment. To learn more about this research, check out the full article!
Cleavage of Amyloid precursor protein by β- and γ-secretases lead to Aβ formation. The widely accepted pathogenic model states that these mutations cause AD via an increase in Aβ formation and accumulation of Aβ in Amyloid plaques. APP mutations cause early onset familial forms of Alzheimer’s disease (FAD) in humans. We generated App−Swedish (Apps) knock−in rats, which carry a pathogenic APP mutation in the endogenous rat App gene. This mutation increases β-secretase processing of APP leading to both augmented Aβ production and facilitation of glutamate release in Apps/s rats, via a β-secretase and APP−dependent glutamate release mechanism. Here, we studied 11 to 14-month-old male and female Apps/s rats. To determine whether the Swedish App mutation leads to behavioral deficits, Apps/s knock-in rats were subjected to behavioral analysis using the IntelliCage platform, an automated behavioral testing system. This system allows behavioral assessment in socially housed animals reflecting a more natural, less stress-inducing environment and eliminates experimenter error and bias while increasing precision of measurements. Surprisingly, a spatial discrimination and flexibility task that can reveal deficits in higher order brain function showed that Apps/s females, but not Apps/s male rats, performed significantly worse than same sex controls. Moreover, female control rats performed significantly better than control and Apps/s male rats. The Swedish mutation causes a significant increase in Aβ production in 14-month-old animals of both sexes. Yet, male and female Apps/s rats showed no evidence of AD−related amyloid pathology. Finally, Apps/s rats did not show signs of significant neuroinflammation. Given that the APP Swedish mutation causes alterations in glutamate release, we analyzed Long-term potentiation (LTP), a long-lasting form of synaptic plasticity that is a cellular basis for learning and memory. Strikingly, LTP was significantly increased in Apps/s control females compared to both Apps/s sexes and control males. In conclusion, this study shows that behavioral performances are sex and App-genotype dependent. In addition, they are associated with LTP values and not Aβ or AD-related pathology. These data, and the failures of anti-Aβ therapies in humans, suggest that alternative pathways, such as those leading to LTP dysfunction, should be targeted for disease-modifying AD therapy.
Dr. David Lowemann, M.Sc, Ph.D., is a co-founder of the Institute for the Future of Human Potential, where he leads the charge in pioneering Self-Enhancement Science for the Success of Society. With a keen interest in exploring the untapped potential of the human mind, Dr. Lowemann has dedicated his career to pushing the boundaries of human capabilities and understanding.
Armed with a Master of Science degree and a Ph.D. in his field, Dr. Lowemann has consistently been at the forefront of research and innovation, delving into ways to optimize human performance, cognition, and overall well-being. His work at the Institute revolves around a profound commitment to harnessing cutting-edge science and technology to help individuals lead more fulfilling and intelligent lives.
Dr. Lowemann’s influence extends to the educational platform BetterSmarter.me, where he shares his insights, findings, and personal development strategies with a broader audience. His ongoing mission is shaping the way we perceive and leverage the vast capacities of the human mind, offering invaluable contributions to society’s overall success and collective well-being.