Current Alzheimer Research - Volume 17, Issue 12, 2020

The dysregulation of calcium signaling mechanisms in neurons has been considered a contributing factor to the pathogenesis evident in early-onset Alzheimer’s Disease (AD). However, considerably less is known concerning the possible impairment of Ca²⁺ mobilization in resident immune cell microglia. This review considers findings which suggest that a prominent pathway for non-excitable microglial cells, store-operated calcium entry (SOCE), is altered in the sporadic form of AD. The patterns of Ca²⁺ mobilization are first discussed with platelet-activating factor (PAF) stimulation of SOCE in adult, fetal and immortalized cell-line, human microglia in the healthy brain. In all cases, PAF was found to induce a rapid transient depletion of Ca²⁺ from endoplasmic reticulum (ER) stores, followed by a sustained entry of Ca²⁺ (SOCE). A considerably attenuated duration of SOCE is observed with ATP stimulation of human microglia, suggested as due to agonist actions on differential subtype purinergic receptors. Microglia obtained from AD brain tissue, or microglia treated with full-length amyloid-β peptide (Aβ42), show significant reductions in the amplitude of SOCE relative to controls. In addition, AD brain and Aβ42-treated microglia exhibit decreased levels of Ca²⁺ release from ER stores compared to controls. Changes in properties of SOCE in microglia could lead to altered immune cell response and neurovascular unit dysfunction in the inflamed AD brain.

Alzheimer disease is the dominant form of elderly dementia. Today all clinical trials that target β-amyloid have failed to indicate that β-amyloid may not be a causative agent in AD pathogenesis. Thus there is a need to search for alternative ways to treat AD patients. Neuronal store-operated calcium entry is a fine-tuning mechanism that regulates intracellular Ca²⁺ content. Recent evidence suggests that store-operated calcium channels may be targeted with pharmacological agents in order to prevent synapse loss, recover long-term potentiation and change behavior. Current mini-review discusses basic chemical structures that modulate intracellular calcium dysbalance via targeting store-operated calcium channels and their applicability as anti-AD pharmacological agents.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder. Although the pathological hallmarks of AD have been identified, the derived therapies cannot effectively slow down or stop disease progression; hence, it is likely that other pathogenic mechanisms are involved in AD pathogenesis. Intracellular calcium (Ca²⁺) dyshomeostasis has been consistently observed in AD patients and numerous AD models and may emerge prior to the development of amyloid plaques and neurofibrillary tangles. Thus, intracellular Ca²⁺ disruptions are believed to play an important role in AD development and could serve as promising therapeutic intervention targets. One of the disrupted intracellular Ca²⁺ signaling pathways manifested in AD is attenuated storeoperated Ca²⁺ entry (SOCE). SOCE is an extracellular Ca²⁺ entry mechanism mainly triggered by intracellular Ca²⁺ store depletion. Maintaining normal SOCE function not only provides a means for the cell to replenish ER Ca²⁺ stores but also serves as a cellular signal that maintains normal neuronal functions, including excitability, neurogenesis, neurotransmission, synaptic plasticity, and gene expression. However, normal SOCE function is diminished in AD, resulting in disrupted neuronal spine stability and synaptic plasticity and the promotion of amyloidogenesis. Mounting evidence suggests that rectifying diminished SOCE in neurons may intervene with the progression of AD. In this review, the mechanisms of SOCE disruption and the associated pathogenic impacts on AD will be discussed. We will also highlight the potential therapeutic targets or approaches that may help ameliorate SOCE deficits for AD treatment.

Alzheimer's disease (AD) is an insidious and progressive neurodegenerative disorder. Dysfunction of central cholinergic neurons, amyloid aggregation and deposition,oxidative stress,and biometal dyshomeostasis has been regarded as the major pathogenic mediators in this devastating disease. However, strategies derived from these hypotheses fail to slow down or stop the progression of AD, warranting a combination of therapies to target multiple etiological factors or examining alternative hypothesis. Store-operated calcium entry (SOCE) is the process by which depletion of calcium in the endoplasmic reticulum (ER) lumen causes an influx of calcium across plasmalemma. Accumulating evidence indicates that neuronal SOCE (nSOCE) is inhibited in family AD (FAD) and the inhibition of which causes instability of dendritic spines and enhances amyloidogenesis. Mutant Presenilin fails to function as an ER calcium leak channel and promotes degradation of stromal interaction molecules (STIM), ER calcium sensors; these effects may account for the repression of nSOCE in FAD. We have demonstrated that activation of autophagy degrades STIM proteins, resulting in a trimming effect on a dendritic arbor, under proteasome inhibition and endoplasmic reticulum stress, which are intimately connected with AD. Thus, we hypothesize that autophagy represses SOCE by degrading STIM proteins, leading to synapse loss in AD. This review article will highlight the roles of SOCE in AD neurodegeneration, the degradative mechanisms of STIM protein, and the therapeutic potential and associated challenge.

Background: Recent evidence points to a possible link between the inflammatory modulatory protein S100B protein and the pathogenesis of Alzheimer’s disease (AD). Objective: To investigate the elevated levels of serum S100B protein among AD in a South Indian cohort and its correlation with severity of cognitive impairment. Methods: A cross-sectional study was conducted with 100 AD patients and 100 age and sex matched healthy controls. Diagnosis of AD was made by a qualified neurologist using NINCDS ADRDA criteria. Measurement of serum S100B protein was performed using solid phase sandwich ELISA method in both cases and controls. Results: Significantly higher prevalence of elevated serum S100B protein 44(44%) (p<0.0001), hypertension 52(52%) (p=0.02), diabetes mellitus 58(58%) (p=0.002), thyroid dysfunction 28(28%) (p=0.009), positive CRP 46(46%) (p<0.0001) and lower mean Mini-Mental State Examination (MMSE) values 20.4±5.1 (p<0.0001) were seen in AD patients compared to controls. Elevated S100B protein levels were significantly associated with Clinical dementia rating (CDR) score 2(34%) (p=0,05) and score 3 (61.3%) (p=0.03) compared to normal levels. After multivariable logistic regression analysis positive C-Reactive Protein (odds: 3.2; 95%CI: 2.8-9.8)(p=0.001), elevated S100B protein (odds: 9.0;95%CI:2.2-35.8) and diabetes mellitus (odd:1.2;95%CI:1.0-4.9)(p<0.0001), were significantly associated with AD. Conclusion: In our study, we established an independent association of elevated serum S100B protein levels with AD. Elevated S100B protein levels higher in CDR score 3.

Background: Individuals from sexual minorities experience health inequalities that have detrimental impacts on their health, especially in the elderly, by exacerbating care needs and symptoms of chronic conditions such as Alzheimer’s disease (AD). Neurocognitive decline due to AD in the sexual minority population remains under-investigated. However, being in a relationship may mitigate the risk of experiencing cognitive impairment. Objective: The aim of this study was to investigate whether cognitive decline and brain atrophy may differ in people from sexual minorities. Methods: Clinical data for this study were selected from the National Alzheimer’s Coordinating Center’s Uniform Data Set and structural MRI data collected across 14 Alzheimer’s Disease Centers. Eighty participants including 20 patients with AD and 20 healthy controls (HC) in same-sex relationships were identified and matched to groups of participants (20 AD and 20 HC) in opposite-sex relationships. The effects of diagnosis and relationship were investigated on all measures. Results: No diagnosis-by-relationship interactions were found on any variable. However, post hoc analyses revealed that the opposite-sex group had grey matter atrophy mainly in medio-temporal areas. In the same-sex group, atrophy also extended to pre-frontal and cingulate areas. The severity of neuropsychiatric symptoms correlated with volume of pre-frontal and insular/temporal areas only in the same-sex group. Conclusion: Neurocognitive decline due to AD may express similarly across individuals, independently of relationship type, thus suggesting a protective role of relational status. However, the same-sex group appeared to be more likely to experience at least one neuropsychiatric symptom and to have atrophy extending to fronto-limbic areas.

Background: Central arterial stiffness is an emerging risk factor of age-related cognitive impairment and Alzheimer’s disease (AD). However, the underlying pathophysiological mechanisms remain unclear. Objective: We tested the hypothesis that carotid arterial stiffness is associated with reduced cerebral blood flow (CBF) and increased cerebrovascular resistance (CVR) in patients with amnestic mild cognitive impairment (MCI), a prodromal stage of AD. Methods: Fifty-four patients with amnestic MCI and 24 cognitively normal subjects (CN) of similar age and sex to MCI patients underwent measurements of CBF and carotid β-stiffness index using ultrasonography and applanation tonometry. Total CBF was measured as the sum of CBF from both the internal carotid and vertebral arteries, and divided by total brain tissue mass (assessed with MRI) to obtain normalized CBF (nCBF). Results: Relative to CN subjects, MCI patients showed lower nCBF (53.3 ± 3.2 vs 50.4±3.4 mL/100 g/min, P < 0.001) and higher CVR (0.143 ± 0.019 vs 0.156 ± 0.023 mmHg/mL/min, P < 0.015). Multiple linear regression analysis showed that nCBF was negatively associated with carotid β-stiffness index (B = -0.822, P < 0.001); CVR was positively associated with carotid systolic pressure (B = 0.001, P < 0.001) after adjustment for age, sex, body mass index, and MCI status. Conclusion: These findings suggest that carotid artery stiffening may contribute at least in part to the reduced nCBF and increased CVR in patients with MCI associated with augmented carotid arterial pulsatility.

Background: Adiponectin has been implicated in the pathophysiology of dementia, especially Alzheimer’s disease. However, the association between cerebrospinal fluid (CSF) adiponectin levels and positron emission tomography (PET) imaging remains unclear. Objective: To explore whether CSF adiponectin levels are associated with ¹¹C-Pittsburgh compound B (PiB) or ¹⁸F-fluorodeoxyglucose (FDG) uptake in amnestic mild cognitive impairment (MCI) subjects. Methods: Thirty-four amnestic MCI subjects underwent PiB-PET, FDG-PET, and CSF analysis. The CSF adiponectin levels were measured using the Bio-Plex 200 suspension array system. PET uptake was assessed for the frontal and temporoparietal lobes and posterior cingulate gyrus, referenced against the cerebellar cortex. The increased brain amyloid burden was defined as a mean uptake value ratio greater than 1.4. Spearman’s rank correlation analysis and a multiple regression model were used to examine the association between CSF adiponectin levels and PiB or FDG uptake. Results: The mean age was 76.3 years; 38.2% were men, and 61.8% were women. A high amyloid burden was identified in 18 (52.9%) subjects. CSF adiponectin levels positively correlated with global FDG uptake (β = 0.45; 95% confidence interval (CI), 0.13 to 0.76, p < 0.01), especially in the parietotemporal lobe and posterior cingulate gyrus (β = 0.70; 95% CI, 0.41 to 0.99, p<0.01, β = 0.33; 95% CI, 0.03 to 0.63, p = 0.03, respectively) after adjusting for covariates, including age, sex, education years, body mass index, vascular risk factors, ApoEε4 status, and PiB status in all amnestic MCI subjects. Conclusion: CSF adiponectin levels were associated with cortical glucose metabolism, particularly in the specific regions that connect with the medial temporal, but not brain amyloid burden in amnestic MCI subjects.

Background: Beta amyloid (Aβ) peptide containing plaque aggregations in the brain are a hallmark of Alzheimer’s Disease (AD). However, Aβ is produced by cell types outside of the brain suggesting that the peptide may serve a broad physiologic purpose. Objective: Based upon our prior work documenting expression of amyloid β precursor protein (APP) in intestinal epithelium we hypothesized that salivary epithelium might also express APP and be a source of Aβ. Methods: To begin testing this idea, we compared human age-matched control and AD salivary glands to C57BL/6 wild type, App^NL-G-F , and APP/PS1 mice. Results: Both male and female AD, App^NL-G-F , and APP/PS1 glands demonstrated robust APP and Aβ immunoreactivity. Female App^NL-G-F mice had significantly higher levels of pilocarpine stimulated Aβ 1-42 compared to both wild type and APP/PS1 mice. No differences in male salivary Aβ levels were detected. No significant differences in total pilocarpine stimulated saliva volumes were observed in any group. Both male and female App^NL-G-F but not APP/PS1 mice demonstrated significant differences in oral microbiome phylum and genus abundance compared to wild type mice. Male, but not female, APP/PS1 and App^NL-G-F mice had significantly thinner molar enamel compared to their wild type counterparts. Conclusion: These data support the idea that oral microbiome changes exist during AD in addition to changes in salivary Aβ and oral health.