Introduction: Dementias are a group of diseases that generate cognitive impairment in patients affecting their quality of life, its most frequent form being Alzheimer's disease (AD). AD accounts for more than half of the cases of dementia worldwide with a significant increase in incidence projected within the next 40 years. It is characterized by a set of histopathological changes consisting of decreased neuronal density along with the accumulation of amyloid beta (Aβ) and tau protein, which compromises cognitive, behavioral, emotional and even motor functions, so it is essential to understand its molecular and clinical relationship. In relation to synaptic plasticity, it has been seen that Aβ oligomers affect its proper functioning. Additionally, calcineurin (CaN), which is a protein involved in the intracellular calcium pathway, has been associated with initial cognitive impairment in AD and increases in later stages as amyloid pathology worsens. Therefore, understanding how its increase and/or decrease may affect AD progression and changes in synaptic plasticity is fundamental to establish possible therapeutic targets. Objectives: To identify in the literature the role of CaN in the processes of synaptic plasticity in preclinical models of AD and thus propose possible changes in the progression of the disease. Methodology: A systematic review of the literature was carried out in different databases (PubMed, Scopus, Web of Science) in studies in animal models in which the relationship of CaN in synaptic plasticity processes in AD models was evidenced. PROSPERO registry: The systematic review protocol was registered in the PROSPERO platform on September 12, 2023, under code CRD42023446993. Results: Initially, 119 articles were identified, from which 42 were selected for analysis. However, only 22 of these articles met the criteria for intervention, indication, and primary outcomes necessary to evaluate Long-Term Potentiation (LTP) and Long-Term Depression (LTD) in various preclinical models of Alzheimer's Disease (AD). Among the selected studies, significant findings included increased calcineurin (CaN) activity following Aβ infusion into the CA1 region of the hippocampus in response to stress (see ref: 59-85% of rats, table 5). Variability in CaN expression was also observed due to alterations in HFS or LFS-induced LTP/LTD, modulated by conditions such as exercise or the use of inhibitors, with statistically significant differences (see ref: p<0.01, table 6). These findings suggest relevant changes in cellular signaling cascades and synaptic plasticity (p<0.05), which could contribute to synaptic deterioration observed in preclinical models of AD. Most analyzed studies indicate that Aβ oligomers inhibit both the induction and expression of LTP. These compounds also promote alterations in intracellular calcium, favoring dysregulated intracellular signaling and morphological changes in synaptic structures. It is noteworthy that CaN activation contributes to LTD, while its inhibition appears to mitigate the acute hippocampal LTP expression deficit induced by Aβ oligomers. As a secondary outcome, this intervention successfully restores synaptic component composition and mitigates associated cognitive decline. Discussion: It has been possible to determine that CaN plays a fundamental role in the pathophysiology of AD by increasing AD progression and altering synaptic plasticity processes, in terms of LTP, LTD and potentiation. In most of the studies found the use of FK506 as a CaN inhibitor effectively reversed the abolition of Aβ-induced LTP expression, however, clinical trials that can corroborate this hypothesis in the clinical setting are required.
