Microglia as a Possible Alternative Therapeutic for Dementia.

Dementia is a syndrome in which there is deterioration in memory, behavior, and the ability to perform everyday activities. Alzheimer's disease and vascular dementia are the most common forms of dementia. There is evidence supporting the hypothesis that inflammatory and immune mechanisms are involved in dementia. Microglia, the resident macrophage tissues in the central nervous system, play a significant role in neuroinflammation and play an important role in amyloid-ß clearance in the brain, and impaired microglial clearance of amyloid-ß has also been shown to be involved in the pathogenesis of Alzheimer's disease. However, there is also abundant evidence that microglia have harmful actions in dementia. Once activated, they can mediate uptake at neuronal synapses. They can also exacerbate tau pathology and secrete deleterious inflammatory factors that can directly or indirectly damage neurons. Thus, depending on the stage of the disease, microglia can act both protectively and detrimentally. Therefore, it is still necessary to continue with studies to better understand the role of microglia in the pathology of dementia. Currently available drugs can only improve cognitive symptoms, have no impact on progression and are not curative, so identifying and studying new therapeutic approaches is important. Considering the role played by microglia in this pathology, it has been pointed out as a possible therapeutic approach. This manuscript aims to address the relationship between microglia and dementia and how this relationship could be used for therapeutic purposes.

Relationship Between Genetic Variants of ACAT1 and APOE with the Susceptibility to Dementia (SADEM Study).

One of the hypotheses that have emerged to explain the origin of dementia relates the disease with altered lipid metabolism, particularly cholesterol. To maintain cholesterol homeostasis, the ACAT1 enzyme has an important function to regulate the production of Aß. Moreover, APOE is the main cholesterol carrier in the brain, and it has been reported as a risk factor for this disease. This study evaluates the relationship between ACAT1 and APOE genetic variants with susceptibility for the development of Alzheimer's disease and other dementias. We examined four ACAT1 polymorphisms (rs2247071, rs2862616, rs3753526, rs1044925) and two in the APOE gene (rs7412, rs429358) in a group of 204 controls and 196 cases of dementia. Our results show one protective haplotype: CGCA (OR = 0.34, 95% CI = 0.23-0.46; p < 0.001) and one risk haplotype: CGGA (OR = 1.87, 95% CI = 1.34-2.60; p < 0.001) for the development of dementia. Subjects identified as APOE-ε4 allele carriers had a higher risk of developing dementia compared with non-carriers, OR = 13.33 (95% CI = 3.14-56.31). The results support the hypothesis that the ACAT1 gene, together with the APOE gene, plays an important role in susceptibility to the development of dementia and shows genetic characteristics of the Mexican population that can be used to identify the population at risk.

ACAT1 as a Therapeutic Target and its Genetic Relationship with Alzheimer's Disease.

BACKGROUND: Alzheimer´s disease (AD) is a chronic and progressive disease which impacts caregivers, families and societies physically, psychologically and economically. Currently available drugs can only improve cognitive symptoms, have no impact on progression and are not curative, so identifying and studying new drug targets is important. There are evidences which indicate disturbances in cholesterol homeostasis can be related with AD pathology, especially the compartmentation of intracellular cholesterol and cytoplasmic cholesterol esters formed by acyl-CoA: cholesterol acyltransferase 1 (ACAT1) can be implicated in the regulation of amyloid-beta (Aß) peptide, involved in AD. Blocking ACAT1 activity, beneficial effects are obtained, so it has been suggested that ACAT1 can be a potential new therapeutic target. The present review discusses the role of cholesterol homeostasis in AD pathology, especially with ACAT inhibitors, and how they have been raised as a therapeutic approach. In addition, the genetic relationship of ACAT and AD is discussed. CONCLUSION: Although there are several lines of evidence from cell-based and animal studies that suggest that ACAT inhibition is an effective way of reducing cerebral Aß, there is still an information gap in terms of mechanisms and concerns to cover before passing to the next level. Additionally, an area of interest that may be useful in understanding AD to subsequently propose new therapeutic approaches is pharmacogenetics; however, there is still a lot of missing information in this area.