Administration of Cholecystokinin B Receptor Agonists Improves Synaptic Plasticity and Cognition of Aged Alzheimer's Disease Mice

Abstract

Dementia generally results in memory loss and other intellectual disabilities. According to Alzheimer’s Disease (AD) International, in 2015 the population suffering from dementia all over the world was nearly 50 million, and this number is expected to triple by 2050. AD, which is the principal cause of dementia, brings a huge challenge to global healthcare. It has become an urgency to develop treatment strategies to alleviate or cure AD.

Combining mutant amyloid precursor protein (APP) gene, presenilin 1 and tau transgenes, the triple-transgenic AD mouse model (3xTg-AD) is one of the most useful research tools for discovering new treatments for AD. 3xTg-AD mice develop intraneuronal amyloid beta (Aβ) pathology at as early as fourth month and show deficits of learning and memory from sixth month.

In this study, we first investigated the cognitive impairments of aged 3xTg-AD mice using Morris water maze (MWM) and novel object recognition (NOR) tasks. MWM is a widely used behavioral paradigm in rodents which enables spatial learning and memory to be studied accurately. The results presented that compared to aged wildtype mice, 1) during training, aged AD mice displayed lower learning ability since they had longer escape latency to locate platform; 2) in retention test, aged AD mice displayed impaired memory retrieval capability because they spent significant less exploratory time in target quadrant where platform used to be positioned. In NOR task, discrimination index (DI) to novel object was computed to evaluate mice’s recognition memory based on their natural tendency to novel object rather than familiar one. We found that DI of aged AD mice was significantly lower than aged wildtype mice, suggesting that aged AD mice showed deficit in recognition memory.

Changing synaptic strength in neural networks builds memory. Long-term potentiation (LTP) is the best-known manifestation of activity-dependent synaptic plasticity. Here we explored the synaptic impairments of theta burst stimulation (TBS) induced LTP using in vitro electrophysiological recording in young and aged AD and wildtype mice. We failed to induce cortical LTP on aged AD mice while succeeded on young controls. However, hippocampal LTP was induced on aged AD mice but smaller than that induced on their young or wildtype control.

Cholecystokinin (CCK) is one of the most abundant neuropeptides in the brain, spreading throughout neocortex, hippocampus and entorhinal cortex (EC). Previous studies have proved that CCK participates in anxiety and food intake as well as several types of learning and memory processes. Earlier work of our lab revealed that CCK-deficient (CCK^−/−) mice lacked neocortical LTP which was rescued by infusion of CCK and displayed associative learning deficits which were also relieved by administration of CCK in a cue-cue associative learning paradigm. Hence, we made the hypothesis that the lack of CCK could imitate symptoms of AD, therefore mice lack of CCK could be used for studying new AD treatments.

To investigate the learning ability of CCK^−/− mice, we further examined CCK^−/− mice with MWM and NOR tasks. It turned out that just like aged AD mice, CCK^−/− mice developed similar deficits of learning and memory compared to littermate control. And these deficits were alleviated through the treatment of CCK B receptor (CCK BR) agonist, CCK-4. Moreover, CCK^−/− mice exhibited impaired hippocampal LTP which was rescued by administration of CCK-4. Afterwards, we further examined whether the rescue effect of CCK-4 could extend to aged 3xTg-AD mice. Thereby we applied CCK-4 on aged 3xTg-AD mice in both MWM and NOR tasks, and discovered that mice treated with CCK-4 performed better than mice treated with vehicle. In addition, applying CCK-4 also recovered impaired cortical LTP of aged 3xTg-AD mice.

However, CCK-4 is not a perfect remedy due to its instability (half-life in the plasma of rodents is 1 min). Therefore, we designed a CCK-4 analogue named LYZ-866, which has enhanced plasma half-life (96 min). Afterwards, we identified that the application of LYZ-866 improved mice’s performance in MWM and NOR tasks and repaired cortical LTP of aged 3xTg-AD mice.

To conclude, the present study provides more evidence to support the role of CCK in LTP induction and memory formation. On the one hand, CCK^−/− mice imitated deficits of learning and memory of aged 3xTg-AD mice; on the other hand, their deficits were alleviated after treatment of CCK-4. This rescue effect was also confirmed on aged 3xTg-AD mice. After being treated with CCK-4, they displayed enhanced LTP and improved performance in behavioral tests. Moreover, we elaborated the rescue effect of a promising novel drug, LYZ-866, to impaired synaptic and cognitive functions of aged 3xTg-AD mice. Although the physiological etiology of CCK in AD still needs to be further investigated, this study sheds light on a potential pharmaceutical candidate for AD and dementia.

Date of Award	14 Jan 2021
Original language	English
Awarding Institution	City University of Hong Kong
Supervisor	Jufang HE (Supervisor) & Patrick KANOLD (External Co-Supervisor)