Current Alzheimer Research - Volume 16, Issue 1, 2019

Background: Presenilin-1 (PSEN-1) is a component of the γ-secretase complex involved in β-amyloid Precursor Protein (AβPP) processing. Usually, Alzheimer's disease (AD)-linked mutations in the PSEN-1 gene lead to the early onset and increase the production of the aggregation-prone peptide Aβ42. However, the PSEN-1 E318G variant has an unclear pathogenic role and is recently reported as a genetic risk factor for AD. In particular, E318G variant presence correlated with increased cerebrospinal fluid (CSF) levels of Total Tau (t-tau) and Phosphorylated Tau (p-tau). Objective: We describe a large Italian family, which we followed from January 2003 to January 2018, with the late-onset AD and the E318G variant, with the aim of assessing E318G-associated CSF or plasma biochemical changes in biomarkers of dementia. Method: CSF Aβ42, t-tau and p-tau, plasma Aβ42 and Aβ40 were assessed by ELISA tests, while CSF amyloid peptides profile was investigated by mass spectrometry. Results: We did not find any changes in CSF biochemical markers (Aβ42, t-tau, p-tau and amyloid peptides) of asymptomatic E318G carriers in 2010 and 2012, but plasma Aβ40 was increased at the same times. From 2003 to 2018, no asymptomatic E318G carrier developed AD. Conclusion: Our follow-up of this family may help elucidate E318G's role in AD and globally points to a null effect of this variant.

Background: Preclinical and clinical evidence suggests that elderly individuals are at increased risk of cognitive decline after general anesthesia. General anesthesia is also believed to be a risk factor for Postoperative Cognitive Dysfunction (POCD) and Alzheimer's Disease (AD). Intranasal administration of insulin, which delivers the drug directly into the brain, improves memory and cognition in both animal studies and small clinical trials. However, how insulin treatment improves cognitive function is poorly understood. Methods: Aged mice were pretreated with intranasal insulin or saline before anesthesia. Propofol was added intraperitoneally to the mice from 7th day of insulin/saline treatment, and general anesthesia was induced and maintained for 2 hours/day for 5 consecutive days. Mice were evaluated at 26th day when the mice were continued on insulin or saline administration for another 15 days. Results: We found that intranasal insulin treatment prevented anesthesia-induced cognitive impairments, as measured by novel object recognition test and contextual-dependent fear conditioning test. Insulin treatment also increased the expression level of Post-synaptic Density Protein 95 (PSD95), as well as upregulated Microtubule-associated Protein-2 (MAP-2) in the dentate gyrus of the hippocampus. Furthermore, we found that insulin treatment restored insulin signaling disturbed by anesthesia via activating PI3K/PDK1/AKT pathway, and attenuated anesthesia-induced hyperphosphorylation of tau at multiple AD-associated sites. We found the attenuation of tau hyperphosphorylation occurred by increasing the level of GSK3β phosphorylated at Ser9, which leads to inactivation of GSK-3β. Conclusion: Intranasal insulin administration might be a promising therapy to prevent anesthesiainduced cognitive deficit in elderly individuals.

Background: Among the protective factors for cognitive decline related to aging and Alzheimer's disease, education level is one of the most prominent. However, the mechanisms underlying the protective effects of education on cognition remain to be elucidated. In this study, we aimed to systematically assess the role of Functional Connectivity (FC) of resting-state brain networks playing in the cognition-protection effect of education. Methods: Data from a battery of neuropsychological tests and functional magnetic resonance imaging in resting-state were acquired in 77 cognitively normal elderly participants from local communities in Beijing, China. Six resting-state networks related to primary function or complex cognition were extracted through independent component analysis. We then explored the relationships between education level, cognition, and FC of these networks. Results: We found that education level was positively associated with a wide range of complex cognitive domains including general mental status, episodic memory, language, attention, executive function and visuospatial processing, and it showed significantly negative correlations with FC of multiple areas in the Default Mode Network (DMN) and Left Frontal-parietal Network (LFP) which are related to complex cognition. And regional connectivity of DMN was significantly negatively correlated with episodic memory performance. Further mediation analysis suggested that higher education level was associated with higher episodic memory performance through lower regional connectivity of DMN. Conclusion: Our findings indicate that inhibitory modulation in the resting-state brain networks related to complex cognition is one of the main routes through which education exerts its protective effects on cognition in normal aging.

Background: Alzheimer’s disease (AD) is the most common cause of dementia in elderly populations. Changes in the expression of the Amyloid Precursor Protein (APP)-cleaving enzymes directly affect the formation of Amyloid Beta (Aβ) plaques, a neuropathological hallmark of AD. Objective: We used peripheral blood from AD patients to investigate the expression of genes related to APP-processing [(β-site APP-cleaving enzyme 1 (BACE1), presenilin1 (PSEN1), and a disintegrin and metalloproteinase family 10 (ADAM10) and 17 (ADAM17)] and the epigenetic genes sirtuin (SIRT)1-3, which regulate Aβ production. Method: Real-time polymerase chain reactions were performed to determine the specific mRNA levels in plasma. The mRNA levels in AD patients were compared to those in healthy persons and assessed in relation to the subjects’ cognitive performance. Results: BACE1 mRNA level in AD subjects was significantly higher than those of healthy controls, whereas ADAM10 level was significantly lower in the AD subjects. The SIRT1 level was significantly decreased, while that of SIRT2 was increased in AD subjects and elderly controls compared to levels in healthy young control. In addition, correlations were found between the expression levels of BACE1, ADAM10 and SIRT1 and cognitive performance scores. Total Aβ (Aβ40+Aβ42) levels and the Aβ40/Aβ42 ratio were significantly increased in the AD subjects, whereas decrease in plasma Aβ42 was found in AD subjects. There was a negative correlation between Aβ40 or total Aβ and Thai Mental State Examination (TMSE) while there was no correlation between Aβ40/Aβ42 ratio or Aβ42 and TMSE. Conclusion: The present findings provide evidence and support for the potential roles of these enzymes that drive Aβ synthesis and for epigenetic regulation in AD progression and development, which can possibly be considered peripheral markers of AD.

Background: β-amyloid (Aβ) aggregation plays an important role in the pathogenesis of Alzheimer’s disease (AD), and astrocytes can significantly inhibit Aβ aggregation. Astrocytic α7 Neuronal Nicotinic Acetylcholine Receptor (nAChR) upregulation detected in the AD brains is closely associated with Aβ deposits. However, the relationships between the astrocytic α7 nAChRs and Aβ aggregation remain unclear. Methods: The Aβ oligomers levels in astrocytic cell lysates and culture medium were measured after treatment with nicotine or co-treatment with a Phosphatidylinositol 3-Kinase (PI3K)-protein kinase B (Akt) inhibitor. The level of αB-Crystallin (Cryab) in astrocytes treated with nicotine for different times or co-treated with α7 nAChR antagonists as well as co-incubated with a PI3K or mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor was determined by western blotting. Results: In this study, nicotine pre-treatment in primary astrocytes markedly inhibited Aβ aggregation and upregulated endogenous astrocytic Cryab, while the nicotine-mediated neuroprotective effect was reversed by pre-treatment with a selective α7 nAChR antagonist. Furthermore, this neuroprotection against Aβ aggregation was suppressed by LY294002, a PI3K inhibitor. Pre-treatment with nicotine significantly increased the levels of phosphorylated Akt, an effector of PI3K in astrocytes. Conclusion: α7 nAChR activation and PI3K/Akt signaling transduction contributed to nicotinemediated neuroprotection against Aβ aggregation by modulating endogenous astrocytic Cryab.

Background: Positron-emission-tomography (PET) using 18F labeled florbetaben allows noninvasive in vivo-assessment of amyloid-beta (Aβ), a pathological hallmark of Alzheimer's disease (AD). In preclinical research, [¹⁸F]-florbetaben-PET has already been used to test the amyloid-lowering potential of new drugs, both in humans and in transgenic models of cerebral amyloidosis. The aim of this study was to characterize the spatial pattern of cerebral uptake of [¹⁸F]-florbetaben in the APPswe/ PS1dE9 mouse model of AD in comparison to histologically determined number and size of cerebral Aβ plaques. Methods: Both, APPswe/PS1dE9 and wild type mice at an age of 12 months were investigated by smallanimal PET/CT after intravenous injection of [¹⁸F]-florbetaben. High-resolution magnetic resonance imaging data were used for quantification of the PET data by volume of interest analysis. The standardized uptake values (SUVs) of [¹⁸F]-florbetaben in vivo as well as post mortem cerebral Aβ plaque load in cortex, hippocampus and cerebellum were analyzed. Results: Visual inspection and SUVs revealed an increased cerebral uptake of [¹⁸F]-florbetaben in APPswe/ PS1dE9 mice compared with wild type mice especially in the cortex, the hippocampus and the cerebellum. However, SUV ratios (SUVRs) relative to cerebellum revealed only significant differences in the hippocampus between the APPswe/PS1dE9 and wild type mice but not in cortex; this differential effect may reflect the lower plaque area in the cortex than in the hippocampus as found in the histological analysis. Conclusion: The findings suggest that histopathological characteristics of Aβ plaque size and spatial distribution can be depicted in vivo using [¹⁸F]-florbetaben in the APPswe/PS1dE9 mouse model.

Introduction: Aging is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular diseases, and neurodegenerative diseases such as Alzheimer’s Disease (AD). AD is a progressive degenerative disorder of the brain and is the most common form of dementia. Methods: To-date no simple, inexpensive and minimally invasive procedure is available to confirm with certainty the early diagnosis of AD prior to the manifestations of symptoms characteristic of the disease. Therefore, if population screening of individuals is to be performed, easily accessible tissues would need to be used for a diagnostic test that would identify those who exhibit altered or aberrant aging profiles that may be indicative of AD risk, so that they can be prioritized for primary prevention. This need for minimally invasive tests could be achieved by targeting saliva, since it is now well recognized that many aging diseases including AD are associated with peripheral biomarkers that are not only restricted to pathology and biomarkers within the brain. Results: Therefore, the aim of this review is to summarize some of the main findings of salivary biomarkers of aging and AD; including various proteins, metabolites, and alterations to DNA and miRNA. The future of healthy aging resides in innovative platforms, biosensors and point-of-care devices that can extract real time information on the health status of an individual. Those platforms may be achieved through the development and validation of novel biomarkers of health using saliva which, although being the least explored for biomedical purposes, has the distinct advantage that it can be self-collected in a non-invasive manner.

Background: Cognitive deficits are correlated with increasing age and become more pronounced for people with mild cognitive impairment (MCI) and dementia caused by Alzheimer's disease (AD). Conventional methods to diagnose cognitive decline (i.e., neuropsychological testing and clinical judgment) can lead to false positives. Tools such as electroencephalography (EEG) offer more refined, objective measures that index electrophysiological changes associated with healthy aging, MCI, and AD. Objective: We sought to review the EEG literature to determine whether visual event-related potentials (ERPs) can distinguish between healthy aging, MCI, and AD. Method: We searched Medline and PyscInfo for articles published between January 2005 and April 2018. Articles were considered for review if they included participants aged 60+ who were healthy older adults or people with MCI and AD, and examined at least one visually elicited ERP component. Results: Our search revealed 880 records, of which 34 satisfied the inclusion criteria. All studies compared cognitive function between at least two of the three groups (healthy older adults, MCI, and AD). The most consistent findings related to the P100 and the P3b; while the P100 showed no differences between groups, the P3b showed declines in amplitude in MCI and AD. Conclusion: Visually elicited ERPs can offer insight into the cognitive processes that decline in MCI and AD. The P3b may be useful in identifying older adults who may develop MCI and AD, and more research should examine the sensitivity and specificity of this component when diagnosing MCI and AD.