Journal of Alzheimer's Disease - Volume 76, issue 4

Authors: Resende, Rosa | Ferreira-Marques, Marisa | Moreira, Patrícia | Coimbra, Judite R.M. | Baptista, Salete J. | Isidoro, Ciro | Salvador, Jorge A.R. | Dinis, Teresa C.P. | Pereira, Cláudia F. | Santos, Armanda E.

Article Type: Research Article

Abstract: Background: A disease-modifying therapy for Alzheimer’s disease (AD) is still an unmet clinical need. The formation of amyloid-β (Aβ) requires the initial cleavage of the amyloid-β protein precursor (AβPP) by BACE1 (beta-site AβPP cleaving enzyme 1), which is a prime therapeutic target for AD. Objective: We aimed to design and develop a selective BACE1 inhibitor suitable to AD treatment. Methods: The new BACE1 inhibitors consist on a chimeric peptide including a sequence related to the human Swedish mutant form of AβPP (AβPPswe) conjugated with the TAT carrier that facilitates cell membrane permeation and the crossing of …the blood-brain barrier. Additionally to the chimeric peptide in the L -form, we developed a D -retroinverso chimeric peptide. The latter strategy, never used with BACE1 inhibitors, is considered to favor a significantly higher half-life and lower immunogenicity. Results: We found that both chimeric peptides inhibit recombinant BACE1 activity and decrease Aβ40/42 production in Neuro-2a (N2A) cells expressing AβPPswe without inducing cytotoxicity. The intraperitoneal administration of these peptides to 3xTg-AD mice decreased plasma and brain Aβ40/42 levels, as well as brain soluble AβPPβ production. Also, a reduction of insoluble Aβ was observed in the brain after chronic treatment. Noteworthy, the chimeric peptides selectively inhibited the AβPP-β cleavage relatively to the proteolysis of other BACE1 substrates such as close homologue of L1 (CHL1) and seizure-related gene 6 (SEZ6). Conclusions: Overall these new BACE1 chimeric peptideshold promising potential as a selective disease-modifying therapy for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, BACE1 inhibitor, chimeric peptide, CHL1, SEZ6

DOI: 10.3233/JAD-200381

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1317-1337, 2020

Authors: Li, Tengfei | Martin, Elodie | Abada, Yah-se | Boucher, Céline | Cès, Aurélia | Youssef, Ihsen | Fenaux, Grégory | Forand, Yona | Legrand, Annaelle | Nachiket, Nadkarni | Dhenain, Marc | Hermine, Olivier | Dubreuil, Patrice | Delarasse, Cécile | Delatour, Benoît

Article Type: Research Article

Abstract: Background: Masitinib is a selective tyrosine kinase inhibitor that modulates mast cells activity. A previous phase II study reported a cognitive effect of masitinib in patients with Alzheimer’s disease. Objective: We aimed to shed light on the mode of action of masitinib in Alzheimer’s disease. Methods/Results: We demonstrated here that chronic oral treatment of APPswe/PSEN1dE9 transgenic mice modeling Alzheimer’s disease restored normal spatial learning performance while having no impacts on amyloid-β loads nor on neuroinflammation. However, masitinib promoted a recovery of synaptic markers. Complete genetic depletion of mast cells in APPswe/PSEN1dE9 mice similarly rescued synaptic …impairments. Conclusion: These results underline that masitinib therapeutic efficacy might primarily be associated with a synapto-protective action in relation with mast cells inhibition. Show more

Keywords: Alzheimer’s disease, cognition, drug evaluation, masitinib, mast cells, preclinical, synapses

DOI: 10.3233/JAD-200466

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1339-1345, 2020

Authors: Mohan, Devi | Yap, Kwong Hsia | Reidpath, Daniel | Soh, Yee Chang | McGrattan, Andrea | Stephan, Blossom C.M. | Robinson, Louise | Chaiyakunapruk, Nathorn | Siervo, Mario | on behalf of DePEC team

Article Type: Research Article

Abstract: Background: A key focus for dementia risk-reduction is the prevention of socio-demographic, lifestyle, and nutritional risk factors. High sodium intake is associated with hypertension and cardiovascular disease (both are linked to dementia), generating numerous recommendations for salt reduction to improve cardiovascular health. Objective: This systematic review aimed to assess, in middle- and older-aged people, the relationship between dietary sodium intake and cognitive outcomes including cognitive function, risk of cognitive decline, or dementia. Methods: Six databases (PubMed, EMBASE, CINAHL, Psych info, Web of Science, and Cochrane Library) were searched from inception to 1 March 2020. Data extraction …included information on study design, population characteristics, sodium reduction strategy (trials) or assessment of dietary sodium intake (observational studies), measurement of cognitive function or dementia, and summary of main results. Risk-of-bias assessments were performed using the National Heart, Lung, and Blood Institute (NHLBI) assessment tool. Results: Fifteen studies met the inclusion criteria including one clinical trial, six cohorts, and eight cross-sectional studies. Studies reported mixed associations between sodium levels and cognition. Results from the only clinical trial showed that a lower sodium intake was associated with improved cognition over six months. In analysis restricted to only high-quality studies, three out of four studies found that higher sodium intake was associated with impaired cognitive function. Conclusion: There is some evidence that high salt intake is associated with poor cognition. However, findings are mixed, likely due to poor methodological quality, and heterogeneous dietary, analytical, and cognitive assessment methods and design of the studies. Reduced sodium intake may be a potential target for intervention. High quality prospective studies and clinical trials are needed. Show more

Keywords: Cognitive dysfunction, dementia, salt, sodium, systematic review

DOI: 10.3233/JAD-191339

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1347-1373, 2020

Authors: Shi, Yun | Zhang, Lei | Gao, Xue | Zhang, Jing | Ben Abou, Matan | Liang, Ge | Meng, Qingcheng | Hepner, Adrian | Eckenhoff, Maryellen F. | Wei, Huafeng

Article Type: Research Article

Abstract: Background/Objective: This study compares the effectiveness and safety of intranasal versus subcutaneous administration of dantrolene in 5XFAD Alzheimer’s disease (AD) mice. Methods: 5XFAD and wild type (WT) B6SJLF1/J mice were treated with intranasal or subcutaneous dantrolene (5 mg/kg, 3×/wk), or vehicle. The early (ETG) and late (LTG) treatment groups began treatment at 2 or 6 months of age, respectively, and both treatment groups finished at12 months of age. Behavior was assessed for olfaction (buried food test), motor function (rotarod), and cognition (fear conditioning, Morris water maze). Liver histology (H & E staining) and function, synaptic proteins, and brain amyloid …immunohistochemistry were examined. Plasma and brain dantrolene concentrations were determined in a separate cohort after intranasal or subcutaneous administration. Results: Intranasal dantrolene achieved higher brain and lower plasma concentrations than subcutaneous administration. Dantrolene administration at both approaches significantly improved hippocampal-dependent and -independent memory in the ETG, whereas only intranasal dantrolene improved cognition in the LTG. Dantrolene treatment had no significant change in the amyloid burden or synaptic proteins and no significant side effects on mortality, olfaction, motor, or liver functions in 5XFAD mice. Intranasal dantrolene treatment significantly ameliorated memory loss when it was started either before or after the onset of AD symptoms in 5XFAD mice. Conclusions: The long-term intranasal administration of dantrolene had therapeutic effects on memory compared to the subcutaneous approach even started after onset of AD symptoms, suggesting use as a disease-modifying drug, without significant effects on amyloid plaques, side effects, or mortality. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dantrolene, intranasal administration

DOI: 10.3233/JAD-200227

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1375-1389, 2020

Authors: Joa, Kyung-Lim | Mankhong, Sakulrat | Kim, Sujin | Moon, Sohee | Lee, Kyoung-Hee | Yoo, Young-Hwan | Hwang, Byeong-Hun | Baek, Jong-Won | Kang, Ju-Hee

Article Type: Research Article

Abstract: Background: Recent evidence indicates brain ischemia is associated with accumulations of abnormal tau and related proteins. However, the effects of aerobic training on these proteins have not been evaluated. Objective: We aimed to evaluate the effect of aerobic exercise on the phosphorylation and acetylation of tau and on the expressions of tau related proteins in a rat stroke model and to compare the effects of aerobic exercise with those observed in our previous study on task specific training (TST). Methods: Twenty-four Sprague– Dawley rats with photothrombotic cortical infarction were used in the current study. The rehabilitation …group (RG) received treadmill training 40 min/day for 28 days, whereas the sedentary group (SG) did not receive any type of training. Functional tests such as the single pellet reaching task, rotarod, and radial arm maze tests were performed weekly for 4 weeks post-infarction. Results: Levels of p-taus396 and p-AMPK were found to be lower in ipsilateral cortices in the RG than in the SG (p  < 0.05). Levels of p-taus262 , Ac-tau, p-GSK3βS9 , p-Akt, p-Sin1, and p-P70-S6K were significantly lower in ipsilateral than in contralateral cortices in the RG (p  < 0.05). Aerobic training also improved motor, balance, and memory functions. Conclusion: Aerobic training inhibited the phosphorylation and acetylation of tau and modulated the expressions of tau related proteins after stroke by modifying the p70-S6K pathway and p-AMPK. By comparison with our previous study on the effects of TST, we have evidence to suggest that TST and aerobic exercise differ, although both types of rehabilitation inhibit tau phosphorylation and acetylation. Show more

Keywords: Aerobic training, dementia, phosphorylated tau, rehabilitation, stroke, tau

DOI: 10.3233/JAD-200250

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1391-1402, 2020

Authors: Nicoli, Charles D. | Howard, Virginia J. | Judd, Suzanne E. | Struck, Joachim | Manly, Jennifer J. | Cushman, Mary

Article Type: Research Article

Abstract: Background: The neuropeptide neurotensin (NT) has been linked to cardiometabolic disease. Cardiovascular risk factors are being recognized as risk factors for cognitive impairment. Objective: To examine the association of the stable precursor of NT, pro-neurotensin/neuromedin N (pro-NT/NMN), with incident cognitive impairment (ICI). Methods: We conducted a prospective nested case-control study in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. In 2003-2007, REGARDS enrolled 30,239 Black and White adults aged ≥45 years. ICI was identified using a 3-test cognitive battery administered biannually. Baseline pro-NT/NMN was measured by immunoassay in 393 cases of ICI and …490 controls after 3.4 years follow up. Multivariable logistic regression was used to calculate odds ratios (OR) of ICI by pro-NT/NMN quartiles. Race, age, and sex differences were studied with stratified models and interaction testing. Results: Pro-NT/NMN was higher in Black participants and those with hypertension and diabetes. Women with a 4th versus 1st-quartile pro-NT/NMN had 2.28-fold increased odds of ICI (95% CI 1.08–4.78) after adjusting for risk factors and incident stroke. There was no association of higher pro-NT/NMN quartiles with ICI in the overall group or men. There were no race or age differences in associations. Conclusion: In this biracial population-based study, elevated systemic pro-NT/NMN was associated with more than doubled risk of ICI in women but not men. Others reported sex-specific associations in women for cardiovascular mortality and diabetes with higher pro-NT/NMN, supporting a role for future research on sex differences in the neurotensinergic system. Show more

Keywords: Biomarkers, case-control studies, cognition disorders, cognitive dysfunction, neuropeptides, neurotensin, prospective studies

DOI: 10.3233/JAD-200456

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1403-1412, 2020

Authors: Falcon, Carles | Grau-Rivera, Oriol | Suárez-Calvet, Marc | Bosch, Beatriz | Sánchez-Valle, Raquel | Arenaza-Urquijo, Eider M. | González-de-Echavarri, José María | Gispert, Juan Domingo | Rami, Lorena | Molinuevo, José Luis

Article Type: Research Article

Abstract: Background: There is increasing evidence that AD progression differs by sex. Objective: The aim of this work was to determine sex differences in the association of baseline levels of cerebrospinal fluid (CSF) biomarkers (Aβ42 , p-tau, YKL-40, sTREM2) with longitudinal brain changes in cognitively unimpaired (CU) older adults. Methods: This pilot study included 36 CU subjects (age 66.5±5.5, 12 male) scanned twice, two years apart. Using a voxel-wise analysis, we determined the sex differences in the association maps between CSF biomarkers and atrophy rates. Results: We did not find differences related to Aβ42 . …We found a greater impact of the rest of CSF biomarkers in areas of the Papez circuit in women versus men. Men showed greater involvement in lateral parietal and paracentral areas. Discussion: Results suggest an early differential progression of brain atrophy between sexes. Further research will elucidate whether the mechanisms responsible for sex-specific atrophy patterns are biological and/or environmental. Show more

Keywords: Cerebrospinal fluid biomarkers, cognitively unimpaired older adults, longitudinal VBM, sex differences, sTREM2, YKL-40

DOI: 10.3233/JAD-200293

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1413-1422, 2020

Authors: Hakim, Md A. | Behringer, Erik J.

Article Type: Research Article

Abstract: Background: Development of Alzheimer’s disease (AD) pathology is associated with impaired blood flow delivery of oxygen and nutrients throughout the brain. Cerebrovascular endothelium regulates vasoreactivity of blood vessel networks for optimal cerebral blood flow. Objective: We tested the hypothesis that cerebrovascular endothelial Gq -protein-coupled receptor (GPCR; purinergic and muscarinic) and K+ channel [Ca2+ -activated (KCa 2.3/SK3 and KCa 3.1/IK1) and inward-rectifying (KIR 2.x)] function declines during progressive AD pathology. Methods: We applied simultaneous measurements of intracellular Ca2+ ([Ca2+ ]i ) and membrane potential (Vm ) in freshly isolated endothelium from posterior cerebral arteries of …3×Tg-AD mice [young, no pathology (1– 2 mo), cognitive impairment (CI; 4– 5 mo), extracellular Aβ plaques (Aβ; 6– 8 mo), and Aβ plaques + neurofibrillary tangles (AβT; 12– 15 mo)]. Results: The coupling of Δ Vm -to-Δ [Ca2+ ]i during AβT pathology was lowest for both sexes but, overall, ATP-induced purinergic receptor function was stable throughout AD pathology. SKCa /IKCa channel function itself was enhanced by ∼20% during AD (Aβ+ AβT) versus pre-AD (Young + CI) in males while steady in females. Accordingly, hyperpolarization-induced [Ca2+ ]i increases following SKCa /IKCa channel activation and Δ [Ca2+ ]i -to-Δ Vm coupling was enhanced by ≥two-fold during AD pathology in males but not females. Further, KIR channel function decreased by ∼50% during AD conditions versus young regardless of sex. Finally, other than a ∼40% increase in females versus males during Aβ pathology, [Ca2+ ]i responses to the mitochondrial uncoupler FCCP were similar among AD versus pre-AD conditions. Conclusion: Altogether, AD pathology represents a condition of altered KCa and KIR channel function in cerebrovascular endothelium in a sex-dependent and sex-independent manner respectively. Show more

Keywords: Cerebral arteries, endothelial cells, potassium channels, sex characteristics

DOI: 10.3233/JAD-200085

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1423-1442, 2020

Authors: Goto, Tetsuya | Kuramoto, Eriko | Dhar, Ashis | Wang, Rachel Pei-Hsuan | Seki, Haruka | Iwai, Haruki | Yamanaka, Atsushi | Matsumoto, Shin-Ei | Hara, Hiromitsu | Michikawa, Makoto | Ohyagi, Yasumasa | Leung, Wai Keung | Chang, Raymond Chuen-Chung

Article Type: Research Article

Abstract: Background: The mesencephalic trigeminal nucleus (Vmes) is not only anatomically adjacent to the locus coeruleus (LC) but is also tightly associated with the function of the LC. The LC can be the first area in which Alzheimer’s disease (AD) develops, although it is unclear how LC neuronal loss occurs. Objective: We investigated whether neuronal death in the Vmes can be spread to adjacent LC in female triple transgenic (3×Tg)-AD mice, how amyloid-β (Aβ) is involved in LC neuronal loss, and how this neurodegeneration affects cognitive function. Methods: The molars of 3×Tg-AD mice were extracted, and the …mice were reared for one week to 4 months. Immunohistochemical analysis, and spatial learning/memory assessment using the Barnes maze were carried out. Results: In 4-month-old 3×Tg-AD mice, aggregated cytotoxic Aβ42 was found in granules in Vmes neurons. Neuronal death in the Vmes occurred after tooth extraction, resulting in the release of cytotoxic Aβ42 and an increase in CD86 immunoreactive microglia. Released Aβ42 damaged the LC, in turn inducing a significant reduction in hippocampal neurons in the CA1 and CA3 regions receiving projections from the LC. Based on spatial learning/memory assessment, after the tooth extraction in the 4-month-old 3×Tg-AD mice, increased latency was observed in 5-month-old 3×Tg-AD mice 1 month after tooth extraction, which is similar increase of latency observed in control 8-month-old 3×Tg-AD mice. Measures of cognitive deficits suggested an earlier shift to dementia-like behavior after tooth extraction. Conclusion: These findings suggest that tooth extraction in the predementia stage can trigger the spread of neurodegeneration from the Vmes, LC, and hippocampus and accelerate the onset of dementia. Show more

Keywords: Alzheimer’s disease, amyloid-β, behavior, locus coeruleus, neurodegeneration, tooth loss, trigeminal nuclei

DOI: 10.3233/JAD-200257

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1443-1459, 2020

Authors: Schwab, Simon | Afyouni, Soroosh | Chen, Yan | Han, Zaizhu | Guo, Qihao | Dierks, Thomas | Wahlund, Lars-Olof | Grieder, Matthias

Article Type: Research Article

Abstract: Background: Semantic memory impairments in semantic dementia are attributed to atrophy and functional disruption of the anterior temporal lobes. In contrast, the posterior medial temporal neurodegeneration found in Alzheimer’s disease is associated with episodic memory disturbance. The two dementia subtypes share hippocampal deterioration, despite a relatively spared episodic memory in semantic dementia. Objective: To unravel mutual and divergent functional alterations in Alzheimer’s disease and semantic dementia, we assessed functional connectivity between temporal lobe regions in Alzheimer’s disease (n  = 16), semantic dementia (n  = 23), and healthy controls (n  = 17). Methods: In an exploratory study, we used a …functional parcellation of the temporal cortex to extract time series from 66 regions for correlation analysis. Results: Apart from differing connections between Alzheimer’s disease and semantic dementia that yielded reduced functional connectivity, we identified a common pathway between the right anterior temporal lobe and the right orbitofrontal cortex in both dementia subtypes. This disconnectivity might be related to social knowledge deficits as part of semantic memory decline. However, such interpretations are preferably made in a holistic context of disease-specific semantic impairments and functional connectivity changes. Conclusion: Despite a major limitation owed to unbalanced databases between study groups, this study provides a preliminary picture of the brain’s functional disconnectivity in Alzheimer’s disease and semantic dementia. Future studies are needed to replicate findings of a common pathway with consistent diagnostic criteria and neuropsychological evaluation, balanced designs, and matched data MRI acquisition procedures. Show more

Keywords: Alzheimer’s disease, functional connectivity, semantic dementia, temporal lobe

DOI: 10.3233/JAD-191113

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1461-1475, 2020