Current Alzheimer Research - Volume 17, Issue 4, 2020

Pathologic calcium (Ca2+) signaling linked to Alzheimer’s Disease (AD) involves the intracellular Ca2+ release channels/ryanodine receptors (RyRs). RyRs are macromolecular complexes where the protein-protein interactions between RyRs and several regulatory proteins impact the channel function. Pharmacological and genetic approaches link the destabilization of RyRs macromolecular complexes to several human pathologies including brain disorders. In this review, we discuss our recent data, which demonstrated that enhanced neuronal RyR2-mediated Ca2+ leak in AD is associated with posttranslational modifications (hyperphosphorylation, oxidation, and nitrosylation) leading to RyR2 macromolecular complex remodeling, and dissociation of the stabilizing protein Calstabin2 from the channel. We describe RyR macromolecular complex structure and discuss the molecular mechanisms and signaling cascade underlying neuronal RyR2 remodeling in AD. We provide evidence linking RyR2 dysfunction with β-adrenergic signaling cascade that is altered in AD. RyR2 remodeling in AD leads to histopathological lesions, alteration of synaptic plasticity, learning and memory deficits. Targeting RyR macromolecular complex remodeling should be considered as a new therapeutic window to treat/or prevent AD setting and/or progression.

Alzheimer’s Disease (AD), a neurodegenerative disorder with high incidence and mortality, is leading its way to the top of the list of the deadliest diseases without an effective disease-modifying drug. Ca2+ dysregulation, specifically abnormal release of Ca2+ via over activated ryanodine receptor (RyR), has been increasingly considered as an alternative upstream mechanism in AD pathology. Consequently, dantrolene, a RyR antagonist and FDA approved drug to treat malignant hyperthermia and chronic muscle spasms, has been shown to ameliorate memory loss in AD transgenic mice. However, the inefficiency of dantrolene to pass the Blood Brain Barrier (BBB) and penetrate the Central Nervous System needs to be resolved, considering its dose-dependent neuroprotection in AD and other neurodegenerative diseases. In this mini-review, we will discuss the current status of dantrolene neuroprotection in AD treatment and a strategy to maximize its beneficial effects, such as intranasal administration of dantrolene.

Mitochondria absorb calcium (Ca2+) at the expense of the electrochemical gradient generated during respiration. The influx of Ca2+ into the mitochondrial matrix helps maintain metabolic function and results in increased cytosolic Ca2+ during intracellular Ca2+ signaling. Mitochondrial Ca2+ homeostasis is tightly regulated by proteins located in the inner and outer mitochondrial membranes and by the cross-talk with endoplasmic reticulum Ca2+ signals. Increasing evidence indicates that mitochondrial Ca2+ overload is a pathological phenotype associated with Alzheimer’s Disease (AD). As intracellular Ca2+ dysregulation can be observed before the appearance of typical pathological hallmarks of AD, it is believed that mitochondrial Ca2+ overload may also play an important role in AD etiology. The high mitochondrial Ca2+ uptake can easily compromise neuronal functions and exacerbate AD progression by impairing mitochondrial respiration, increasing reactive oxygen species formation and inducing apoptosis. Additionally, mitochondrial Ca2+ overload can damage mitochondrial recycling via mitophagy. This review will discuss the molecular players involved in mitochondrial Ca2+ dysregulation and the pharmacotherapies that target this dysregulation. As most of the current AD therapeutics are based on amyloidopathy, tauopathy, and the cholinergic hypothesis, they achieve only symptomatic relief. Thus, determining how to reestablish mitochondrial Ca2+ homeostasis may aid in the development of novel AD therapeutic interventions.

Despite decades of research and effort, there is still no effective disease-modifying treatment for Alzheimer’s Disease (AD). Most of the recent AD clinical trials were targeting amyloid pathway, but all these trials failed. Although amyloid pathology is a hallmark and defining feature of AD, targeting the amyloid pathway has been very challenging due to low efficacy and serious side effects. Alternative approaches or mechanisms for our understanding of the major cause of memory loss in AD need to be considered as potential therapeutic targets. Increasing studies suggest that Ca2+ dysregulation in AD plays an important role in AD pathology and is associated with other AD abnormalities, such as excessive inflammation, increased ROS, impaired autophagy, neurodegeneration, synapse, and cognitive dysfunction. Ca2+ dysregulation in cytosolic space, Endoplasmic Reticulum (ER) and mitochondria have been reported in the context of various AD models. Drugs or strategies, to correct the Ca2+ dysregulation in AD, have been demonstrated to be promising as an approach for the treatment of AD in preclinical models. This review will discuss the mechanisms of Ca2+ dysregulation in AD and associated pathology and discuss potential approaches or strategies to develop novel drugs for the treatment of AD by targeting Ca2+ dysregulation.

Background: β-Site APP-cleaving enzyme 1 (BACE1) is a key enzyme involved in the pathophysiology of Type 2 Diabetes Mellitus (T2DM) and Mild Cognitive Impairment (MCI). We aimed to investigate the potential associations of plasma BACE1 levels and BACE1 gene polymorphism with different cognitive performances in T2DM patients with MCI. Methods: The recruited 186 T2DM subjects were divided into 92 MCI group and 94 healthy-cognition controls, according to the Montreal Cognitive Assessment (MoCA) scores. Sociodemographic characteristics, clinical parameters and neuropsychological tests were assessed. BACE1 C786G gene polymorphism and plasma BACE1 level were determined. Results: Compared to controls, MCI patients exhibited higher plasma BACE1 levels. Plasma BACE1 levels were negatively associated with MoCA, Clock Drawing Test and Logical Memory Test scores, whereas positively associated with Trail Making Test-B time in the MCI group (all p<0.05), after adjusting fasting blood glucose, glycosylated hemoglobin, and homeostasis model assessment of insulin resistance by C-peptide. Multivariable logistic regression analysis showed a significant trend towards increased MCI risk with high plasma BACE1 level in T2DM patients (OR = 1.492, p = 0.027). The plasma BACE1 levels of GG and GC genotypes were obviously higher than that of CC genotype in T2DM-MCI patients (p = 0.035; p = 0.026, respectively). Conclusion: Increased plasma BACE1 levels were associated with poor overall cognition functions, especially visuospatial abilities, visual/logical memory and executive functions in T2DM-MCI patients. Additionally, elevated plasma BACE1 level was a risk factor for MCI in T2DM patients, and might be influenced by BACE1 C786G gene mutations.

Background: Sedentary life-style is a significant public health issue. It increases the incidence of type-2 diabetes mellitus (DM2) and systemic arterial hypertension (SAH), which in turn may impair physical and mental health. In fact, disrupted glucose metabolism is characteristic of Alzheimer’s dementia, and it is often dubbed as type-3 diabetes. Objective: The purpose of this study was to assess the level of activity, body composition, cardiovascular risk and cognitive profile of patients with DM2 and/or SAH. The study was cross-sectional design. Method: The sample consisted of 120 individuals which 35% men and 65% women, with an average of 64±9 years old and 60±11 years old, respectively. Various parameters were evaluated such as anthropometric variables, pedometer recordings and brief cognitive screening battery (BCSB), which assesses the immediate memory, verbal fluency, learning, late memory and recognition. Chi-square and Fisher's exact test were applied to observe possible differences between men and women. In addition to Kruskall-Wallis, in the comparison between patients with SAH; DM2 and SAH + DM2. Results: A high rate of physical inactivity was found among those enrolled in this project. Females were characterized by increased body fat, whereas men displayed visceral fat excess. BCSB demonstrated reduced verbal fluency, late memory and recognition, with women presenting significantly worse results. Conclusion: Low level of daily physical activity is apparently correlated with obesity, elevated cardiovascular risk, and cognitive dysfunction.

Background: Subjective Memory Impairment (SMI) may tremendously increase the risk of Alzheimer’s Disease (AD). The full understanding of the neuromechanism of SMI will shed light on the early intervention of AD. Methods: In the current study, 23 Healthy Controls (HC), 22 SMI subjects and 24 amnestic Mild Cognitive Impairment (aMCI) subjects underwent the comprehensive neuropsychological assessment and the resting-state functional magnetic resonance imaging scan. The difference in the connectivity of the Default Mode Network (DMN) and Functional Connectivity (FC) from the Region of Interest (ROI) to the whole brain were compared, respectively. Results: The results showed that HC and SMI subjects had significantly higher connectivity in the region of the precuneus area compared to aMCI subjects. However, from this region to the whole brain, SMI and aMCI subjects had significant FC decrease in the right anterior cingulum, left superior frontal and left medial superior frontal gyrus compared to HC. In addition, this FC change was significantly correlated with the cognitive function decline in participants. Conclusion: Our study indicated that SMI subjects had relatively intact DMN connectivity but impaired FC between the anterior and posterior brain. The findings suggest that long-distance FC is more vulnerable than the short ones in the people with SMI.

Background: Cognitive capacities in Alzheimer’s Disease (AD) are impaired by an epigenetic blockade mediated by histone deacetylase 2 (HDAC2), which prevents the transcription of genes that are important for synaptic plasticity. Objective: Investigation of the functional relationship between cell adhesion molecule L1 and HDAC2 in AD. Methods: Cultures of dissociated cortical and hippocampal neurons from wild-type or L1-deficient mice were treated with Aβ1-42 for 24 h. After removal of Aβ1-42 cells were treated with the recombinant L1 extracellular domain (rL1) for 24 h followed by immunohistochemistry, western blotting, and reverse transcription PCR to evaluate the interaction between L1 and HDAC2. Results: Aβ and HDAC2 protein levels were increased in APPSWE/L1+/- mutant brains compared to APPSWE mutant brains. Administration of the recombinant extracellular domain of L1 to cultured cortical and hippocampal neurons reduced HDAC2 mRNA and protein levels. In parallel, reduced phosphorylation levels of glucocorticoid receptor 1 (GR1), which is implicated in regulating HDAC2 levels, was observed in response to L1 administration. Application of a glucocorticoid receptor inhibitor reduced Aβ-induced GR1 phosphorylation and prevented the increase in HDAC2 levels. HDAC2 protein levels were increased in cultured cortical neurons from L1-deficient mice. This change could be reversed by the administration of the recombinant extracellular domain of L1. Conclusion: Our results suggest that some functionally interdependent activities of L1 and HDAC2 contribute to ameliorating the phenotype of AD by GR1 dephosphorylation, which leads to reduced HDAC2 expression. The combined findings encourage further investigations on the beneficial effects of L1 in the treatment of AD.

Background: Anti-amyloid-β (Aβ) monoclonal antibodies (mAbs) are currently in development for treating Alzheimer’s disease. Objectives: To address the complexity of Aβ target engagement profiles, improve the understanding of crenezumab Pharmacokinetics (PK) and Aβ Pharmacodynamics (PD) in the brain, and facilitate comparison of anti-Aβ therapies with different binding characteristics. Methods: A mechanistic mathematical model was developed describing the distribution, elimination, and binding kinetics of anti-Aβ mAbs and Aβ (monomeric and oligomeric forms of Aβ1-40 and Aβ1-42) in the brain, Cerebrospinal Fluid (CSF), and plasma. Physiologically meaningful values were assigned to the model parameters based on the previous data, with remaining parameters fitted to clinical measurements of Aβ concentrations in CSF and plasma, and PK/PD data of patients undergoing anti-Aβ therapy. Aβ target engagement profiles were simulated using a Monte Carlo approach to explore the impact of biological uncertainty in the model parameters. Results: Model-based estimates of in vivo affinity of the antibody to monomeric Aβ were qualitatively consistent with the previous data. Simulations of Aβ target engagement profiles captured observed mean and variance of clinical PK/PD data. Conclusion: This model is useful for comparing target engagement profiles of different anti-Aβ therapies and demonstrates that 60 mg/kg crenezumab yields a significant increase in Aβ engagement compared with lower doses of solanezumab, supporting the selection of 60 mg/kg crenezumab for phase 3 studies. The model also provides evidence that the delivery of sufficient quantities of mAb to brain interstitial fluid is a limiting step with respect to the magnitude of soluble Aβ oligomer neutralization.