PSD-95: A Possible Treatment for Alzheimer's?

Neurodegenerative diseases are affecting the geriatric population in the world at an alarming rate. They impair the brain from functioning as it should and cause severe distress to those affected by them. These diseases worsen the health of the affected individual over time and cause a lot of distress to the individuals themselves and their close ones. Many of these diseases are mentioned regularly such as Parkinson’s disease and Alzheimer’s disease. According to Alzheimer’s Association, there are 6.7 million individuals in the United States who are 65 years or older and have Alzheimer’s disease. Unfortunately, there is no known cure for Alzheimer’s disease even though many treatments have tried to slow the progression of Alzheimer's. Due to the lack of a definitive cure, does that mean that 6.7 million people and their families will have to live the rest of their lives fighting a battle against Alzheimer’s without any help in sight? Or can the post-synaptic density protein 95 (PSD-95) help fight this battle against Alzheimer’s?

The article "Pin1 Binding to Phosphorylated PSD-95 Regulates the Number of Functional Excitatory Synapses" by Delgado et al. was presented by Dr. Delgado in detail about the effects of the interaction of PIN1 with PSD-95. When talking about PSD-95 specifically, Delgado et al. state that PSD-95 is involved in the organization of signaling complexes downstream of NMDA receptors. More specifically, it is mentioned that PSD-95 is involved in the development of functional excitatory synapses (Delgado et al., 2020). Delgado et al. then talk about the role of PSD-95 in the induction and expression of synaptic plasticity in pyramidal neurons. They further elaborate that even though the precise molecular mechanisms regulating PSD-95 stability at synapses are not fully understood, PSD-95 is essential for bidirectional synaptic plasticity (Delgado et al., 2020). When focusing on the excitatory capabilities of PSD-95, Delgado et al. state that overexpression of PSD-95 in pyramidal CA1 neurons produces results of enhanced excitatory synaptic transmission. This is extremely important when discussing Alzheimer's disease as the synapses between neurons degenerate due to the presence of β-amyloid.

The study "PSD-95 Protects Synapses from β-Amyloid" aimed to investigate the effect of PSD-95 on β-amyloid and its resulting synaptic depression. Dore et al. aimed to show the possible interference that PSD-95 might have on β-amyloid as PSD-95 is shown to increase synaptic transmission. Dore et al. infected hippocampal slices with a virus that produces β-amyloid and let the infected slices produce β-amyloid. About 18-24 hours later, whole-cell recordings were obtained simultaneously from two neurons, one that was infected and one that was not infected. Results showed that infected neurons had reduced synaptic transmission compared to non-infected control neurons. However, neurons expressing both the β-amyloid-producing virus and PSD-95 displayed an increase in synaptic transmission compared to non-infected control neurons (Dore et al., 2021). The researchers further examined whether PSD-95 enhances transmission or blocks the effects of β-amyloid by recording from GluA1 knockout tissues. The findings demonstrated that PSD-95-induced synaptic potentiation is dependent on GluA1. Notably, neurons that expressed both the β-amyloid-producing virus and PSD-95 did not exhibit significant depression and no synaptic potentiation, suggesting that PSD-95 blocked the depression induced by β-amyloid. The study's results provide new insight into the possible neuroprotective role of PSD-95 in blocking the effects of β-amyloid-induced synaptic depression. (Dore et al., 2021).

The second article was really interesting when viewing it in light of Delgado et al.’s work as Delgado et al. focused on the effects of the interaction of PIN1 with PSD-95. Contrary to that, Dore et al. focused on showing the possible interference that PSD-95 might have on β-amyloid induced depression. Unlike the former study, the latter sheds light on the therapeutic potential of PSD-95, demonstrating that it can mitigate the harmful effects of β-amyloid, which is a hallmark feature of Alzheimer's disease. This finding holds promise for the development of a curative intervention for Alzheimer's, thereby providing much-needed help for patients and their families battling Alzheimer’s.

References

2023 alzheimer's disease facts and figures. (2023). Alzheimer's & Dementia, 19(4), 1598–1695. https://doi.org/10.1002/alz.13016

Delgado, J. Y., Nall, D., & Selvin, P. R. (2020). Pin1 Binding to Phosphorylated PSD-95 Regulates the Number of Functional Excitatory Synapses. Frontiers in Molecular Neuroscience, 13. https://doi.org/10.3389/fnmol.2020.00010

Dore, K., Carrico, Z., Alfonso, S., Marino, M., Koymans, K., Kessels, H. W., & Malinow, R. (2021). PSD-95 protects synapses from β-amyloid. Cell Reports, 35(9), 109194. https://doi.org/10.1016/j.celrep.2021.109194