Current Alzheimer Research - Volume 17, Issue 10, 2020

Objectives: Beta-amyloid (Aβ) peptides are most toxic to cells in oligomeric form. It is commonly accepted that oligomers can form ion channels in cell membranes and allow calcium and other ions to enter cells. The activation of other mechanisms, such as apoptosis or lipid peroxidation, aggravates the toxicity, but it itself can result from the same initial point, that is, ion disturbance due to an increased permeability of membranes. However, experimental studies of membrane channels created by Aβ are surprisingly limited. Methods: Here, we report a novel flow cytometry technique which can be used to detect increased permeability of membranes to calcium induced by the exposure to amyloid peptides. Calcium entry into the liposome is monitored using calcium-sensitive fluorescent probe. Undamaged lipid membranes are not permeable to calcium. Liposomes that are prepared in a calcium-free medium become able to accumulate calcium in a calcium-containing medium only after the formation of channels. Results: Using this technique, we demonstrated that the addition of short amyloid fragment Ab25-35, which is known for its extreme toxicity on cultured neurons, readily increased membrane permeability to calcium. However, neither similarly sized peptide Ab22-35 nor full-length peptide Aβ1-42 were producing channels. The formation of channels was observed in the membranes made of phosphatidylserine, a negatively charged lipid, but not in membranes made of the neutral phosphatidylcholine. Discussion: We have analyzed several issues which could be critical for understanding the pathogenesis of Alzheimer's disease, specifically 1) the need for a negatively charged membrane to produce the ion channel; 2) the potential role of the aggregated form in cellular toxicity of Aβ peptides; 3) channelforming ability of multiple degradation products of amyloid; 4) non-specificity of ion channels formed by amyloid peptides. Potential targets of channel-forming oligomers appear to be intracellular and are organelles well-known for dysfunction in Alzheimer's disease (mitochondria and lysosomes). In fact, lysosomes can also be the producers of degraded amyloid. Provided speculations support the hypothesis that neuronal toxicity can be caused by the degradation products of beta-amyloid.

Background: Survival in patients with dementia is variable. Statins are a cornerstone of cardiovascular prevention. However, the effect of statins on mortality and risk for stroke in patients with dementia is not clear. Objective: The aim of the study was to analyse the association between the use of statins and the risk of all-cause death and first ischemic stroke in patients diagnosed with dementia. Methods: A longitudinal cohort study of 48 771 patients based on combined Swedish registries was conducted. The association between the incident use of statins one year prior to dementia diagnosis, allcause mortality and first ischemic stroke was examined using propensity score-matched flexible parametric or Cox hazard survival models and is presented with hazard ratios and corresponding 95% confidence intervals. Results: After propensity score matching, incident users of statins (n=1412) had a lower risk of all-cause death (HR 0.82, 95% CI 0.74-0.91) and ischemic stroke (HR 0.62, 95% CI 0.43-0.89) compared to matched non-users (n=4482). In stratified analysis, the protective association between incident statin use and survival was observed in men, patients older than 75 years, with Alzheimer's disease and vascular dementia. Furthermore, we observed a protective association between incident use of statins and first ischemic stroke risk in men, patients older than 75 years and with mixed dementia. There was a graded association between cumulative doses of statins and mortality. Conclusion: The use of statins might be beneficial for the survival and ischemic stroke risk in patients with dementia in a dose-dependent manner.

Background: Amyloid PET allows for the assessment of amyloid β status in the brain, distinguishing true Alzheimer's disease from Alzheimer's disease-mimicking conditions. Around 15-20% of patients with clinically probable Alzheimer's disease have been found to have no significant Alzheimer's pathology on amyloid PET. However, a limited number of studies had been conducted on this subpopulation in terms of clinical progression. Objective: We investigated the risk factors that could affect the progression to dementia in patients with amyloid-negative amnestic mild cognitive impairment (MCI). Methods: This study was a single-institutional, retrospective cohort study of patients over the age of 50 with amyloid-negative amnestic MCI who visited the memory clinic of Asan Medical Center with a follow-up period of more than 36 months. All participants underwent brain magnetic resonance imaging (MRI), detailed neuropsychological testing, and fluorine-18[F18]-florbetaben amyloid PET. Results: During the follow-up period, 39 of 107 patients progressed to dementia from amnestic MCI. In comparison with the stationary group, the progressed group had a more severe impairment in verbal and visual episodic memory function and hippocampal atrophy, which showed an Alzheimer's diseaselike pattern despite the lack of evidence for significant Alzheimer's disease pathology. Voxel-based morphometric MRI analysis revealed that the progressed group had a reduced gray matter volume in the bilateral cerebellar cortices, right temporal cortex, and bilateral insular cortices. Conclusion: Considering the lack of evidence of amyloid pathology, clinical progression of these subpopulation may be caused by other neuropathologies such as TDP-43, abnormal tau or alpha synuclein that lead to neurodegeneration independent of amyloid-driven pathway. Further prospective studies incorporating biomarkers of Alzheimer's disease-mimicking dementia are warranted.

Objective: Alzheimer disease (AD) is a chronic neurodegenerative disorder that affects millions of individuals worldwide. Symptoms include memory dysfunction and deficits in attention, planning, language, and overall cognitive function. Olfactory dysfunction is a common symptom of AD and evidence supports that it is an early marker. Furthermore, olfactory bulb and entorhinal cortex atrophy are well described in AD. However, in AD, no studies have assessed the olfactory cortex as a whole and if sex effects are observed. Methods: Magnetic Resonance Imaging was used to scan 39 participants with an average age of 72 years and included men and women. AAL Single-Subject Atlas (implemented in PNEURO tool - PMOD 3.8) was used to determine the volume of the olfactory cortex and the hippocampus. Olfactory cortex volume was lower in both men and women AD cases compared with controls. This decrease was more apparent in the left olfactory cortex and was influenced by age. As expected, hippocampal volume was also significantly reduced in AD. However, this was only observed in the male cohort. A significant correlation was observed between levels of education and hippocampal volume in controls that were not detected in the AD participants. Asymmetry was observed in the olfactory cortex volume when comparing left and right volumes in both the control and AD participants, which was not observed in the hippocampus. Results: These data highlight the importance of the role of olfactory cortical atrophy in the pathogenesis of AD and the interplay between the olfactory deficits and degeneration of olfactory regions in the brain.

Background: Alzheimer's disease (AD) is one of the worst neurodegenerative disorders worldwide, with extracellular senile plaques (SP), subsequent intracellular neurofibrillary tangles (NFTs) and final neuron loss and synaptic dysfunction as the main pathological characteristics. Excessive apoptosis is the main cause of irreversible neuron loss. Thus, therapeutic intervention for these pathological features has been considered a promising strategy to treat or prevent AD. Dihydroartemisin (DHA) is a widely used first-line drug for malaria. Our previous study showed that DHA treatment significantly accelerated Aβ clearance, improved memory and cognitive deficits in vivo and restored autophagic flux both in vivo and in vitro. Methods: The present study intended to explore the neuroprotective effect of DHA on neuron loss in APP/PS1 double-transgenic mice and the underlying mechanisms involved. Transmission electron microscope (TEM) analysis showed that DHA significantly reduced the swollen endoplasmic reticulum (ER) in APP/PS1 mice. Western blot analysis indicated that DHA upregulated the level of NeuN, NeuroD, MAP2, and synaptophysin and promoted neurite outgrowth. Meanwhile, DHA greatly corrected the abnormal levels of Brain-derived neurotrophic factor (BDNF) and rescued the neuronal loss in the hippocampal CA1 area. Western blot analysis revealed that DHA notably down-regulated the protein expression of full length caspase-3, cleaved caspase-3 and Bax. In parallel, the expression of the anti-apoptotic protein Bcl-2 increased after oral DHA treatment. Results:Altogether, these results indicate that DHA protected AD mice from neuron loss via promoting the expression of BDNF and other neuroplasticity-associated proteins and suppressing the inhibition of neuronal apoptosis.

Background: Copy number variations (CNVs) play an important role in the genetic etiology of various neurological disorders, including Alzheimer's disease (AD). Type 2 diabetes mellitus (T2DM) and major depressive disorder (MDD) were shown to have share mechanisms and signaling pathways with AD. Objective: We aimed to assess CNVs regions that may harbor genes contributing to AD, T2DM, and MDD in 67 Saudi familial and sporadic AD patients, with no alterations in the known genes of AD and genotyped previously for APOE. Methods: DNA was analyzed using the CytoScan-HD array. Two layers of filtering criteria were applied. All the identified CNVs were checked in the Database of Genomic Variants (DGV). Results: A total of 1086 CNVs (565 gains and 521 losses) were identified in our study. We found 73 CNVs harboring genes that may be associated with AD, T2DM or MDD. Nineteen CNVs were novel. Most importantly, 42 CNVs were unique in our studied cohort existing only in one patient. Two large gains on chromosomes 1 and 13 harbored genes implicated in the studied disorders. We identified CNVs in genes that encode proteins involved in the metabolism of amyloid-β peptide (AGRN, APBA2, CR1, CR2, IGF2R, KIAA0125, MBP, RER1, RTN4R, VDR and WISPI) or Tau proteins (CACNAIC, CELF2, DUSP22, HTRA1 and SLC2A14). Conclusion: The present work provided information on the presence of CNVs related to AD, T2DM, and MDD in Saudi Alzheimer's patients.

Background: Few works studied the directed whole-brain interaction between different brain regions of Alzheimer's disease (AD). Here, we investigated the whole-brain effective connectivity and studied the graph metrics associated with AD. Methods: Large-scale Granger causality analysis was conducted to explore abnormal whole-brain effective connectivity of patients with AD. Moreover, graph-theoretical metrics including smallworldness, assortativity, and hierarchy, were computed from the effective connectivity network. Statistical analysis identified the aberrant network properties of AD subjects when compared against healthy controls. Results: Decreased small-worldness, and increased characteristic path length, disassortativity, and hierarchy were found in AD subjects. Conclusion: This work sheds insight into the underlying neuropathological mechanism of the brain network of AD individuals such as less efficient information transmission and reduced resilience to a random or targeted attack.

Background: Bulbous neuritic changes in neuritic plaques have already been described, and their possible effect on the clinical course of the disease has been discussed. Objective: In our study, we focused on the location and density of these structures in patients with only Alzheimer's disease (AD) and patients with AD in comorbidity with synucleinopathies. Methods: Utilizing immunohistochemistry and confocal microscopy, we evaluated differences of neocortical and archicortical neuritic plaques and the frequency of bulbous changes in the archicortex of 14 subjects with Alzheimer's disease (AD), 10 subjects with the Lewy body variant of Alzheimer's disease (AD/DLB), and 4 subjects with Alzheimer's disease with amygdala Lewy bodies (AD/ALB). Also, the progression and density of neuritic changes over the time course of the disease were evaluated. Results: We found structural differences in bulbous dystrophic neurites more often in AD/DLB and AD/ALB than in pure AD cases. The bulbous neuritic changes were more prominent in the initial and progressive phases and were reduced in cases with a long clinical course. Conclusion: Our results indicate that there is a prominent difference in the shape and composition of neocortical and archicortical neuritic plaques and, moreover, that bulbous neuritic changes can be observed at a higher rate in AD/DLB and AD/ALB subjects compared to pure AD subjects. This observation probably reflects that these subacute changes are more easily seen in the faster clinical course of AD patients with comorbidities.