The Potential Links Between Alcohol and Alzheimer’s Disease

 

               In a recent research presentation by Dr. Jessica Hoffman, she discussed how AMPA receptors bound to TARP y-8 regulate voluntary alcohol intake in mice. Specifically, the study focused on the differences between the responses of the male and female mice. The experiments resulted in a lack of response from the female mice, while male mice lessened their alcohol intake when exposed to the JNJ drug.

                The researchers tested a selective inhibitor of TARP y-8 called JNJ-55511118, an invasive modulator that inhibited the AMPA receptors bound to TARP y-8. The mice were then exposed to operant self-administration of sweetened alcohol.  This allowed the researchers to measure motivation and reinforcement. They used various methods for giving the mice access to said alcohol, such as lever presses and head pokes. The results showed that JNJ significantly reduced alcohol self-administration in male mice yet did not reduce alcohol intake in female. To ensure the drug was not reducing all motivated behavior, they tested mice on sucrose-only self-administration and found that JNJ did not reduce sucrose responding in either sex. The researchers also ruled out motor impairment through an open-field locomotor test.

               The researchers found that their results suggested that the CaMKII-TARP y-8–AMPAR pathway supports chronic alcohol self-administration. During the talk, Dr. Hoffman suggested a possible outlet for these results in Alzheimer’s research. After digging deeper into this, I found a study by another researcher who had explored the topic. Dr. Sanna and his team found that “Alcohol use disorder (AUD) quickens the pace of Alzheimer’s disease progression when paired with genetic susceptibility,” according to their paper, “A History of Repeated Alcohol Intoxication Promotes Cognitive Impairment and Gene Expression Signatures of Disease Progression in the 3xTg Mouse Model of Alzheimer’s Disease.” In this study, the researchers took Alzheimer’s-model mice and repeatedly exposed them to alcohol vapor chambers over many weeks, then tested their memory. They found that the Alzheimer’s mice who were exposed to alcohol lost their memory much earlier than they normally would. This result surprised me, as I initially thought that introducing a depressant to a disease like Alzheimer’s would slow memory degradation. While AMPARs were not directly measured, the study shows that alcohol accelerates Alzheimer’s by increasing excitatory signaling, which AMPARs contribute to.

Both this study and Dr. Hoffman’s research show that alcohol dysregulates glutamatergic signaling, especially AMPA receptor-related pathways. They both demonstrate that alcohol pushes neurons towards hyperexcitability in both addiction and Alzheimer’s circuits. Dr. Sanna’s team found that alcohol accelerates Alzheimer’s by dysregulating gene networks that increase excitatory signaling and inflammation, while Dr. Hoffman’s study showed that alcohol-reinforced behavior depends on TARP y-8-bound AMPARs. Together, these results suggest alcohol heavily affect the glutamatergic AMPA receptor-mediated mechanisms. Continuing research into this subject would be very interesting, possibly even providing new treatments for Alzheimer’s disease or other related conditions.

 

                                                                        References:

Hoffman, J. L., Faccidomo, S., Saunders, B. L., Taylor, S. M., Kim, M., & Hodge, C. W. (2021). Inhibition of AMPA receptors (AMPARs) containing transmembrane AMPAR regulatory protein γ‑8 with JNJ‑55511118 shows preclinical efficacy in reducing chronic repetitive alcohol self‑administration. Alcoholism: Clinical and Experimental Research, 45(7), 1424–1435. https://doi.org/10.1111/acer.14639

Scripps Research Communications Office. (2023, June 12). Alcohol in excess hastens Alzheimer’s progression. Neuroscience News. https://neurosciencenews.com/alcohol-genetics-alzheimers-23448