Journal of Alzheimer's Disease - Volume 58, issue 4

Authors: Oliveira, Joana | Costa, Márcio | de Almeida, Maria Soares Cachide | da Cruz e Silva, Odete A.B. | Henriques, Ana Gabriela

Article Type: Review Article

Abstract: Altered protein phosphorylation states of several proteins are closely associated with Alzheimer’s disease (AD). Among these are the amyloid-β protein precursor (AβPP) and the tau protein. In fact, altered protein phosphorylation states already provide strong biomarkers for AD diagnosis, as is the case with hyperphosphorylated tau. It follows that modulating signaling cascades provides an attractive avenue for exploring novel therapeutic strategies. This review focuses on some of the major protein kinases and protein phosphatases relevant to AD. Of particular relevance, posttranslational modifications dynamically regulate protein activity, subcellular localization, and stability. Protein phosphorylation states can mediate complex formation as well as …regulate protein function, and this is important for cellular physiology but can likewise contribute to the development of neuropathological conditions. Furthermore, applying a system approach provides a more comprehensive understanding of the signaling events associated with AD and highlights possible convergence points that may contribute to the different AD pathological hallmarks. Show more

Keywords: AβPP binding proteins, Alzheimer’s disease, amyloid cascade hypothesis, amyloid-β protein precursor, biomarkers, protein kinase, protein phosphatase, tau

DOI: 10.3233/JAD-170176

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 953-978, 2017

Authors: Vega, Irving E. | Cabrera, Laura Y. | Wygant, Cassandra M. | Velez-Ortiz, Daniel | Counts, Scott E.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common type of dementia among individuals 65 or older. There are more than 5 million diagnosed cases in the US alone and this number is expected to triple by 2050. Therefore, AD has reached epidemic proportions with significant socioeconomic implications. While aging in general is the greatest risk factor for AD, several additional demographic factors that have contributed to the rise in AD in the US are under study. One such factor is associated with the relatively fast growth of the Latino population. Several reports indicate that AD is more prevalent among blacks and …Latinos. However, the reason for AD disparity among different ethnic groups is still poorly understood and highly controversial. The Latino population is composed of different groups based on nationality, namely South and Central America, Mexico, and Caribbean Hispanics. This diversity among the Latino population represents an additional challenge since there are distinct characteristics associated with AD and comorbidities. In this review, we aim to bring attention to the intersection between social determinants of health and genetic factors associated with AD within the Latino community. We argue that understanding the interplay between identified social determinants of health, co-morbidities, and genetic factors could lead to community empowerment and inclusiveness in research and healthcare services, contributing to improved diagnosis and treatment of AD patients. Lastly, we propose that inserting a neuroethics perspective could help understand key challenges that influence healthcare disparities and contribute to increased risk of AD among Latinos. Show more

Keywords: Alzheimer’s disease, health disparities, healthcare, Latinos, social determinants of health

DOI: 10.3233/JAD-161261

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 979-992, 2017

Authors: Macedo, Arthur Cassa | Balouch, Sara | Tabet, Naji

Article Type: Review Article

Abstract: Sleep disturbances are routinely encountered in Alzheimer’s disease (AD) and affect about 25–40% of patients in the mild-to-moderate stages of the disease. In many, sleep pathology may represent a symptom of the underlying neurodegeneration. However, a history of sleep disruption occurring years prior to onset of cognitive symptoms could represent a potential risk factor for AD. The aim of the present narrative review was to evaluate current evidence linking sleep disturbances with AD development and to understand the mechanisms that may contribute to this. Although the mechanisms by which poor sleep may contribute to AD genesis is not fully understood, …emerging evidence linking disturbances in the sleep wake cycle with Aβ deposition is shedding light on the relationship between sleep pathology and the subsequent development of AD. Aβ burden appears to be enhanced by sleep-wake cycle disruptions and is suspected as being an important mechanism by which sleep disruptions contribute in AD development. Other mechanisms triggered by sleep disruption may also be involved in AD development, such as brain hypoxia, oxidative stress, circadian activity rhythms disturbances, overexpression of orexins, and blood-brain barrier impairment. Further understanding of the link between sleep disturbances and future development of AD is still needed before sleep disturbances are clearly marked as a preventable risk factor for AD. In these circumstances, early lifestyle interventions to help increase the quantity and quality of sleep may have a favorable outcome on decreasing the incidence of AD and this needs to be investigated further. Show more

Keywords: Alzheimer’s disease, dementia, risk factors, sleep, sleep wake disorders

DOI: 10.3233/JAD-161287

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 993-1002, 2017

Authors: Tang, Mengxi | Taghibiglou, Changiz

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder of the elderly. As the prevalence of AD rises in the 21st century, there is an urgent need for the development of effective pharmacotherapies. Currently, drug treatments target the symptoms of the disease and do not modify or halt the disease progress. Thus, natural compounds have been investigated for their ability to treat AD. This review examines the efficacy of curcumin, a polyphenol derived from turmeric herb, to treat AD. We summarize the in vivo and in vitro research describing the mechanisms of action in which curcumin modifies AD pathology: curcumin …inhibits the formation and promotes the disaggregation of amyloid-β plaques, attenuates the hyperphosphorylation of tau and enhances its clearance, binds copper, lowers cholesterol, modifies microglial activity, inhibits acetylcholinesterase, mediates the insulin signaling pathway, and is an antioxidant. In conclusion, curcumin has the potential to be more efficacious than current treatments. However, its usefulness as a therapeutic agent may be hindered by its low bioavailability. If the challenge of low bioavailability is overcome, curcumin-based medications for AD may be in the horizon. Show more

Keywords: Alzheimer’s disease, amyloid-β, curcumin, turmeric, tau protein

DOI: 10.3233/JAD-170188

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1003-1016, 2017

Authors: Skrabana, Rostislav | Kovacech, Branislav | Filipcik, Peter | Zilka, Norbert | Jadhav, Santosh | Smolek, Tomas | Kontsekova, Eva | Novak, Michal

Article Type: Short Communication

Abstract: Animal models of neurodegeneration induced by neuronal expression of truncated tau protein emerge as an important tool for understanding the pathogenesis of human tauopathies and for therapy development. Here we highlight common features of truncated tau models and make a critical assessment of possible pitfalls in their analysis. Particularly, the amount of soluble tau oligomers, which are suspected to be neurotoxic agents participating on the spreading of pathology inside the brain, may be overestimated due to a post-lysis oxidative tau oligomerization. Using a mouse brain lysate spiked with recombinant truncated and full length tau forms, we show that tau oligomers …might inadvertently be produced during the isolation procedure. This finding is further corroborated by the analysis of brain lysates originated from a mouse model expressing truncated tau variant. Our results underline the necessity of thiol-protecting conditions during the analysis of tau oligomers involved in the etiopathogenesis of various tauopathies including Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, protein tau, tauopathy, transgenic models

DOI: 10.3233/JAD-161124

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1017-1025, 2017

Authors: Siedlak, Sandra L. | Jiang, Yinfei | Huntley, Mikayla L. | Wang, Luwen | Gao, Ju | Xie, Fei | Liu, Jingyi | Su, Bo | Perry, George | Wang, Xinglong

Article Type: Short Communication

Abstract: Transmembrane Protein 230 (TMEM230) is a newly identified protein associated with Parkinson’s disease (PD) found in Lewy bodies and Lewy neurites of patients with PD or dementia with Lewy body disease. However, TMEM230 has not yet been investigated in the most common neurodegenerative disorder, Alzheimer’s disease (AD). Here, we demonstrate that the expression of TMEM230 is specifically increased in neurons in AD patients. Importantly, both granulovacuolar degeneration (GVD) and dystrophic neurites (DNs), two prominent characteristic pathological structures associated with AD, contain TMEM230 aggregates. TMEM230 immunoreactivity can be detected in neurofibrillary tangles-containing neurons and hyperphosphorylated tau positive DNs. TMEM230 accumulation is …also noted around senile plaques. These findings identifying TMEM230 as a component of GVD and DNs suggest TMEM230 dysregulation as a likely mechanism playing an important role in the pathogenesis of AD. Show more

Keywords: Alzheimer’s disease, dystrophic neurites, granulovacuolar degeneration, neurofibrillary tangles, senile plaques, TMEM230

DOI: 10.3233/JAD-170190

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1027-1033, 2017

Authors: Liu, Collin Y. | Ohki, Yu | Tomita, Taisuke | Osawa, Satoko | Reed, Bruce R. | Jagust, William | Van Berlo, Victoria | Jin, Lee-Way | Chui, Helena C. | Coppola, Giovanni | Ringman, John M.

Article Type: Research Article

Abstract: Background: The presenilin-1 protein (PS1) is the catalytic unit of γ -secretase implicated in the production of abnormally long forms of amyloid-β (Aβ), including Aβ42 , proteins thought critical in the pathogenesis of Alzheimer’s disease (AD). In AD of autosomal dominant inheritance, the majority of pathogenic mutations have been found in the PSEN1 gene within which the location of the mutation can provide clues as to the mechanism of pathogenesis. Objective: To describe clinical features of two novel mutations in the transmembrane portion 1 (TMD-1) of PSEN1 as well as biochemical features in one and …neuropathological findings in the other. Methods: Two index patients with young onset AD with an autosomal dominant pattern of inheritance underwent clinical and imaging assessments, as well as PSEN1 sequencing. Postmortem examination was completed in one patient. An artificial construct in which the P88L mutation was introduced was created to examine its effects on γ -secretase cleavage. Results: Two novel variants in TMD-1 (P88L and V89L) were identified in affected probands. The neuropathological findings of AD were confirmed in the V89L mutation. Both patients presented around age 40 with early short-term memory deficits followed by seizures and corticospinal tract signs. The P88L mutation additionally featured early myoclonus followed by Parkinsonism. The causal role of the P88L mutation is supported by demonstration that this mutation dramatically increased Aβ42 and decreased APP and Notch intracellular domain production in vitro . Conclusion: Changes in a single amino acid in codons 88 and 89 of TMD-1 can result in young-onset AD. The TMD-1 of PS1 is a region important for the γ -secretase cleavage of Aβ. Show more

Keywords: Autosomal dominant, familial Alzheimer’s disease, gamma-secretase, P88L, presenilin-1 (PSEN1), transmembrane domain, V89L

DOI: 10.3233/JAD-161203

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1035-1041, 2017

Authors: Ivachtchenko, Alexandre V. | Okun, Ilya | Aladinskiy, Vladimir | Ivanenkov, Yan | Koryakova, Angela | Karapetyan, Ruben | Mitkin, Oleg | Salimov, Ramiz | Ivashchenko, Andrey

Article Type: Research Article

Abstract: Discovery of 5-HT6 receptor subtype and its exclusive localization within the central nervous system led to extensive investigations of its role in Alzheimer’s disease, schizophrenia, and obesity. In the present study, we present preclinical evaluation of a novel highly-potent and highly-selective 5-HT6 R antagonist, AVN-492. The affinity of AVN-492 to bind to 5-HT6 R (K i  = 91 pM) was more than three orders of magnitude higher than that to bind to the only other target, 5-HT2B R, (K i  = 170 nM). Thus, the compound displayed great 5-HT6 R selectivity against all other serotonin receptor subtypes, and is extremely specific …against any other receptors such as adrenergic, GABAergic, dopaminergic, histaminergic, etc. AVN-492 demonstrates good in vitro and in vivo ADME profile with high oral bioavailability and good brain permeability in rodents. In behavioral tests, AVN-492 shows anxiolytic effect in elevated plus-maze model, prevents an apomorphine-induced disruption of startle pre-pulse inhibition (the PPI model) and reverses a scopolamine- and MK-801-induced memory deficit in passive avoidance model. No anti-obesity effect of AVN-492 was found in a murine model. The data presented here strongly indicate that due to its high oral bioavailability, extremely high selectivity, and potency to block the 5-HT6 receptor, AVN-492 is a very promising tool for evaluating the role the 5-HT6 receptor might play in cognitive and neurodegenerative impairments. AVN-492 is an excellent drug candidate to be tested for treatment of such diseases, and is currently being tested in Phase I trials. Show more

Keywords: 5-HT6 receptor, Alzheimer’s disease, antagonists, anti-anxiety agents, central nervous system agents, memory enhancement, obesity, schizophrenia

DOI: 10.3233/JAD-161262

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1043-1063, 2017

Authors: Musaeus, Christian S. | Shafi, Mouhsin M. | Santarnecchi, Emiliano | Herman, Susan T. | Press, Daniel Z.

Article Type: Research Article

Abstract: Seizures occur at a higher frequency in people with Alzheimer’s disease (AD) but overt, clinically obvious events are infrequent. Evidence from animal models and studies in mild cognitive impairment suggest that subclinical epileptic discharges may play a role in the clinical and pathophysiological manifestations of AD. In this feasibility study, the neurophysiological and cognitive effects of acute administration of levetiracetam (LEV) are measured in patients with mild AD to test whether it could have a therapeutic benefit. AD participants were administered low dose LEV (2.5 mg/kg), higher dose LEV (7.5 mg/kg), or placebo in a double-blind, within-subject repeated measures study with EEG …recorded at rest before and after administration. After administration of higher dose of LEV, we found significant decreases in coherence in the delta band (1–3.99 Hz) and increases in the low beta (13–17.99 Hz) and the high beta band (24–29.99 Hz). Furthermore, we found trends toward increased power in the frontal and central regions in the high beta band (24–29.99 Hz). However, there were no significant changes in cognitive performance after this single dose administration. The pattern of decreased coherence in the lower frequency bands and increased coherence in the higher frequency bands suggests a beneficial effect of LEV for patients with AD. Larger longitudinal studies and studies with healthy age-matched controls are needed to determine whether this represents a relative normalization of EEG patterns, whether it is unique to AD as compared to normal aging, and whether longer term administration is associated with a beneficial clinical effect. Show more

Keywords: Alzheimer’s disease, coherence, EEG, levetiracetam, power

DOI: 10.3233/JAD-160742

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1065-1076, 2017

Authors: Pertl, Marie-Theres | Benke, Thomas | Zamarian, Laura | Delazer, Margarete

Article Type: Research Article

Abstract: In this study, we investigated the effects of age and of mild cognitive impairment (MCI) on decision making under risk by adopting a task representing real-life health-related situations and involving complex numerical information. Moreover, we assessed the relationship of real-life decision making to other cognitive functions such as number processing, executive functions, language, memory, and attention. For this reason, we compared the performance of 19 healthy, relatively younger adults with that of 18 healthy older adults and the performance of the 18 healthy older adults with that of 17 patients with MCI. Results indicated difficulties in real-life decision making for …the healthy older adults compared with the healthy, relatively younger adults. Difficulties of patients with MCI relative to the healthy older adults arose in particular in difficult items requiring processing of frequencies and fractions. Significant effects of age and of MCI in processing frequencies were also evident in a ratio number comparison task. Decision-making performance of healthy participants and of the patient group correlated significantly with number processing. There was a further significant correlation with executive functions for the healthy participants and with reading comprehension for the patients. Our results suggest that healthy older individuals and patients with MCI make less advantageous decisions when the information is complex and high demands are put on executive functions and numerical abilities. Moreover, we show that executive functions and numerical abilities are not only essential in laboratory gambling tasks but also in more realistic and ecological decision situations within the health context. Show more

Keywords: Aging, decision making, executive functions, mild cognitive impairment, numeracy

DOI: 10.3233/JAD-170119

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1077-1087, 2017