What if one day, you couldn’t remember anymore?

What if one day, you couldn’t remember anymore? Memories of family, life, love, identity, and education- all becoming more and more unfamiliar. The abilities to learn and remember are aspects of life that are utilized every single day, but are often taken for granted. In the United States, 1 in 9 people age 65 and older has Alzheimer’s dementia1. Alzheimer’s disease is a form of dementia that is characterized by neurodegeneration of the hippocampus, resulting in decline of memory, thinking, and reasoning skills. 

In order to determine what mechanisms are responsible for synapse degradation in the hippocampus, identification of the neural components that strengthen a synapse are crucial to proposing a treatment method. Long term potentiation is a form of synaptic plasticity that results in the strengthening of a synapse by an increase of postsynaptic density 95 (PSD95), which stabilizes synaptic changes in long term potentiation by increasing NMDA/AMPA receptors of excitatory synapses. Increases in PSD95 also result in dendritic spine growth, thus strengthening the excitatory synapse. In an individual with Alzheimer’s, hippocampal excitatory neurons undergo long term depression (LTD) by excessively decreasing PSD95, thus resulting in a weakened synapse. 

In the article, “Pin1 Binding to Phosphorylated PSD-95 Regulates the Number of Functional Excitatory Synapses”, Delgado et. al investigate the mechanisms responsible for the regulation of PSD-95 at synapses, and what implications such mechanisms may have on potential treatments for neurodegenerative diseases. Pin1 is an enzyme that is known for its involvement in diseases such as Alzheimer’s, leading to investigation of its involvement with PSD-95. Delgado et. al exhibit that phosphorylation of PSD95 allows Pin1 to bind and cause long term depression by decreasing dendritic PSD95 and number of functional excitatory synapses. Additionally, knocking out Pin1 showed an increase in size and number of post synaptic spines, which could imply a potential treatment for degenerative diseases such as Alzheimer’s.

It is important to note that Pin1 plays a role in multiple aspects of cellular functioning- particularly cell cycle regulation and survival. In “Inverse Correlation between Alzheimer’s Disease and Cancer”, Zablocka explains that Pin1 KO mice showed a resistance to cancer, however they displayed neurodegenerative Alzheimer's-like symptoms. This finding suggests that Pin1 has a crucial regulatory mechanism. Zablocka details that Pin1 is responsible for maintaining a trans-conformation of tau and APP neuronal proteins, which promote functional neuron activity. A cis-conformation of APP results in an increase of B-Amyloid, which is characteristic of Alzheimer’s dementia. Inducing overexpression of Pin1 in the KO mice resulted in a decreased level of B-Amyloid; thus concluding that Pin1 plays a significant role in neuronal regulatory mechanisms- despite its influence on PSD. The increase in number of synaptic spines as a result of Pin1 inhibition could be a result of lack of regulatory mechanisms within the neuron- not necessarily beneficial to the strengthening of synapses. 

Pin1’s role in LTD and LTP can be considered for treatment and regulation of neurodegeneration, given its implications on conformational changes which influence B-Amyloid; however, more detailed signaling cascades such as Pin1’s influence on Wnt signaling and beta-catenins can be further investigated to further target the mechanisms of neurodegeneration and LTP.

References:

https://link.springer.com/article/10.1007/s12035-021-02544-1

https://www.frontiersin.org/articles/10.3389/fnmol.2020.00010/full