Current Alzheimer Research - Volume 16, Issue 5, 2019

Background: Various neurodegenerative diseases, including Alzheimer’s disease (AD), are related to abnormal hyperphosphorylated microtubule-associated protein tau accumulation in brain lesions. Recent studies have focused on toxicity caused by another post-translational modification (PTM), acetylation of the lysine (K) residues of tau protein. Because there are numerous acetylation sites, several studies have introduced mimics of tau acetylation using amino acid substitutions from lysine to glutamine (Q). However, human tau protein contains over 20 acetylation sites; thus, investigation of the effects of an acetylated tau is difficult. Objective: Here, the authors in silico evaluated acetylation effects using SIFT, PolyPhen-2 and PROVEAN which can estimate the effects of amino acid substitutions based on the sequence homology or protein structure in tau isoforms. In addition, they also investigated 27 acetylation effects on the amyloid formation of tau proteins using Waltz. Results: 15 acetylation mimics were estimated to be the most detrimental, which indicates that there may be novel pathogenic acetylation sites in the human tau protein. Interestingly, the deleterious effect of acetylation mimics was different according to the type of isoforms. Furthermore, all acetylation mimics were predicted to be a region of amyloid formation at the codons 274-279 of human tau protein. Notably, acetylation mimic of codon 311 (K311Q) induced the formation of an additional amyloid region located on codons 306-311 of the human tau protein. Conclusion: To the best of our knowledge, this is the first simultaneous in-silico evaluation of the acetylation state of 27 human tau protein residues.

Background: Alzheimer’s Disease (AD) is the most common type of dementia characterized by amyloid plaques containing Amyloid Beta (Aβ) peptides and neurofibrillary tangles containing tau protein. In addition to neuronal loss, Cerebral Amyloid Angiopathy (CAA) commonly occurs in AD. CAA is characterized by Aβ deposition in brain microvessels. Recent studies have suggested that exosomes (cell-derived vesicles containing a diverse cargo) may be involved in the pathogenesis of AD. Objective: Isolate and characterize brain-derived exosomes from a transgenic mouse model of AD that presents CAA. Methods: Exosomes were isolated from serum obtained from 13-month-old wild type and AD transgenic female mice using an exosome precipitation solution. Characterization of exosomal proteins was performed by western blots and dot blots. Results: Serum exosomes were increased in transgenic mice compared to wild types as determined by increased levels of the exosome markers flotillin and alix. High levels of neuronal markers were found in exosomes, without any difference any between the 2 groups. Markers for endothelial-derived exosomes were decreased in the transgenic model, while astrocytic-derived exosomes were increased. Exosome characterization showed increased levels of oligomeric Aβ and oligomeric and monomeric forms tau on the transgenic animals. Levels of amyloid precursor protein were also increased. In addition, pathological and phosphorylated forms of tau were detected, but no difference was observed between the groups. Conclusion: These data suggest that monomeric and oligomeric forms of Aβ and tau are secreted into serum via brain exosomes, most likely derived from astrocytes in the transgenic mouse model of AD with CAA. Studies on the implication of this event in the propagation of AD are underway.

Background and Objective: D-dimer prompts fibrinolysis system, which is involved in Alzheimer’s disease and the complications of type 2 diabetic patients, especially among those with carotid artery plaques. Hence, this study aims to investigate the role of D-dimer in early cognitive impairment among type 2 diabetic patients with carotid artery plaques. Methods: A total of 175 Chinese patients with type 2 diabetes were recruited and divided into two groups according to the Montreal Cognitive Assessment score. Demographic data were collected, plasma D-dimer was tested through VIDAS D-dimer New, neuropsychological tests were examined, and carotid artery plaques were detected by ultrasound and further stratified by vulnerability and level. Results: A total of 67 types 2 diabetic patients with Mild Cognitive Impairment (MCI) displayed significantly increased plasma D-dimer levels compared with their health-cognition controls (p = 0.011). Plasma D-dimer concentration was negatively related with Digit Span Test scores in diabetic patients with vulnerable plaques (r=-0.471, p=0.023) and Stroop Color Word Test C (number) in diabetic patients with stable plaques (r=-0.482, p<0.001). Multivariable regression analysis further showed that D-dimer concentration was an independent factor of diabetic MCI with carotid artery plaque (p=0.005), and D-dimer concentration especially contributed to the high risk of MCI with vulnerable plaques (p=0.028) or high levels of carotid plaque (p=0.023). Conclusion: Elevated D-dimer level predicts the high risk of early cognitive impairment in type 2 diabetic patients with carotid artery plaques, especially vulnerable plaques or high levels of carotid plaques.

Background: There is growing evidence that the gut microbiota may play an important role in neurodegenerative diseases such as Alzheimer’s disease. However, how these commensals influence disease risk and progression still has to be deciphered. Objective: The objective of this review was to summarize current knowledge on the interplay between gut microbiota and retinoic acid. The latter one represents one of the important micronutrients, which have been correlated to Alzheimer’s disease and are used in initial therapeutic intervention studies. Methods: A selective overview of the literature is given with the focus on the function of retinoic acid in the healthy and diseased brain, its metabolism in the gut, and the potential influence that the bioactive ligand may have on microbiota, gut physiology and, Alzheimer’s disease. Results: Retinoic acid can influence neuronal functionality by means of plasticity but also by neurogenesis and modulating proteostasis. Impaired retinoid-signaling, therefore, might contribute to the development of diseases in the brain. Despite its rather direct impact, retinoic acid also influences other organ systems such as gut by regulating the residing immune cells but also factors such as permeability or commensal microbiota. These in turn can also interfere with retinoid-metabolism and via the gutbrain- axis furthermore with Alzheimer’s disease pathology within the brain. Conclusion: Potentially, it is yet too early to conclude from the few reports on changed microbiota in Alzheimer’s disease to a dysfunctional role in retinoid-signaling. However, there are several routes how microbial commensals might affect and might be affected by vitamin A and its derivatives.

Alzheimer’s disease (AD) is a neurodegenerative disorder linked to protein misfolding and aggregation. AD is pathologically characterized by senile plaques formed by extracellular Amyloid-β (Aβ) peptide and Intracellular Neurofibrillary Tangles (NFT) formed by hyperphosphorylated tau protein. Extensive synaptic loss and neuronal degeneration are responsible for memory impairment, cognitive decline and behavioral dysfunctions typical of AD. Amyloidosis has been implicated in the depression of acetylcholine synthesis and release, overactivation of N-methyl-D-aspartate (NMDA) receptors and increased intracellular calcium levels that result in excitotoxic neuronal degeneration. Current drugs used in AD treatment are either cholinesterase inhibitors or NMDA receptor antagonists; however, they provide only symptomatic relief and do not alter the progression of the disease. Aβ is the product of Amyloid Precursor Protein (APP) processing after successive cleavage by β- and γ-secretases while APP proteolysis by α-secretase results in non-amyloidogenic products. According to the amyloid cascade hypothesis, Aβ dyshomeostasis results in the accumulation and aggregation of Aβ into soluble oligomers and insoluble fibrils. The former are synaptotoxic and can induce tau hyperphosphorylation while the latter deposit in senile plaques and elicit proinflammatory responses, contributing to oxidative stress, neuronal degeneration and neuroinflammation. Aβ-protein-targeted therapeutic strategies are thus a promising disease-modifying approach for the treatment and prevention of AD. This review summarizes recent findings on Aβ-protein targeted AD drugs, including β-secretase inhibitors, γ-secretase inhibitors and modulators, α-secretase activators, direct inhibitors of Aβ aggregation and immunotherapy targeting Aβ, focusing mainly on those currently under clinical trials.

Background: Alzheimer’s disease (AD) is associated with extracellular accumulation and aggregation of amyloid β (Aβ) peptides ultimately seeding in senile plaques. Recent data show that their direct precursor C99 (βCTF) also accumulates in AD-affected brain as well as in AD-like mouse models. C99 is consistently detected much earlier than Aβ, suggesting that this metabolite could be an early contributor to AD pathology. C99 accumulates principally within endolysosomal and autophagic structures and its accumulation was described as both a consequence and one of the causes of endolysosomalautophagic pathology, the occurrence of which has been documented as an early defect in AD. C99 was also accompanied by C99-derived C83 (αCTF) accumulation occurring within the same intracellular organelles. Both these CTFs were found to dimerize leading to the generation of higher molecular weight CTFs, which were immunohistochemically characterized in situ by means of aggregate-specific antibodies. Discussion: Here, we discuss studies demonstrating a direct link between the accumulation of C99 and C99-derived APP-CTFs and early neurotoxicity. We discuss the role of C99 in endosomal-lysosomalautophagic dysfunction, neuroinflammation, early brain network alterations and synaptic dysfunction as well as in memory-related behavioral alterations, in triple transgenic mice as well as in newly developed AD animal models. Conclusion: This review summarizes current evidence suggesting a potential role of the β -secretasederived APP C-terminal fragment C99 in Alzheimer’s disease etiology.

Background: Racial/ethnic minorities have among the highest risks for Alzheimer disease and dementia, but remain underrepresented in clinical research studies. Objective: To synthesize the current evidence on strategies to recruit and retain racial/ethnic minorities in Alzheimer disease and dementia clinical research. Methods: We conducted a systematic review by searching CINAHL, EMBASE, MEDLINE, PsycINFO, and Scopus. We included studies that met four criteria: (1) included a racial/ethnic minority group (African American, Latino, Asian, American Indian or Alaska Native, and Native Hawaiian or Other Pacific Islander); (2) implemented a recruitment or retention strategy for Alzheimer disease or dementia clinical research; (3) conducted within the U.S.; and (4) published in a peer-reviewed journal. Results: Of the 19 included studies, 14 (73.7%) implemented recruitment strategies and 5 (26.3%) implemented both recruitment and retention strategies. Fifteen studies (78.9%) focused on African Americans, two (10.6%) on both African Americans and Latinos, and two (10.5%) on Asians. All the articles were rated weak in the study quality. Four major themes were identified for the recruitment strategies: community outreach (94.7%), advertisement (57.9%), collaboration with health care providers (42.1%), and referral (21.1%). Three major themes were identified for the retention strategies: follow-up communication (15.8%), maintain community relationship (15.8%), and convenience (10.5%). Conclusion: Our findings highlight several promising recruitment and retention strategies that investigators should prioritize when allocating limited resources, however, additional well-designed studies are needed. By recruiting and retaining more racial/ethnic minorities in Alzheimer disease and dementia research, investigators may better understand the heterogeneity of disease progression among marginalized groups. PROSPERO registration #CRD42018081979.