Journal of Alzheimer's Disease - Volume 54, issue 3

Authors: Estrada, Lisbell D. | Chamorro, David | Yañez, María José | Gonzalez, Marcelo | Leal, Nancy | von Bernhardi, Rommy | Dulcey, Andrés E. | Marugan, Juan | Ferrer, Marc | Soto, Claudio | Zanlungo, Silvana | Inestrosa, Nibaldo C. | Alvarez, Alejandra R.

Article Type: Research Article

Abstract: One of the pathological hallmarks of Alzheimer’s disease (AD) is the presence of amyloid plaques, which are deposits of misfolded and aggregated amyloid-beta peptide (Aβ). The role of the c-Abl tyrosine kinase in Aβ-mediated neurodegeneration has been previously reported. Here, we investigated the therapeutic potential of inhibiting c-Abl using imatinib. We developed a novel method, based on a technique used to detect prions (PMCA), to measure minute amounts of misfolded-Aβ in the blood of AD transgenic mice. We found that imatinib reduces Aβ-oligomers in plasma, which correlates with a reduction of AD brain features such as plaques and oligomers accumulation, …neuroinflammation, and cognitive deficits. Cells exposed to imatinib and c-Abl KO mice display decreased levels of β-CTF fragments, suggesting that an altered processing of the amyloid-beta protein precursor is the most probable mechanism behind imatinib effects. Our findings support the role of c-Abl in Aβ accumulation and AD, and propose AD-PMCA as a new tool to evaluate AD progression and screening for drug candidates. Show more

Keywords: Alzheimer’s disease, amyloid-beta peptide, amyloid-beta protein precursor, c-Abl tyrosine kinase, imatinib, oligomers, PMCA

DOI: 10.3233/JAD-151087

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1193-1205, 2016

Authors: Baker, Siân | Polanco, Juan Carlos | Götz, Jϋrgen

Article Type: Research Article

Abstract: In Alzheimer’s disease, the distribution of neurofibrillary tangles, a histological hallmark comprised of phosphorylated forms of the protein tau, follows a distinct pattern through anatomically connected brain regions. The well-documented correlation between the severity of tau pathology and disease progression implies a prion-like seeding and spreading mechanism for tau. Experimentally, this has been addressed in transgenic mice by the injection of protein lysates isolated from brains of transgenic mice or patients with tauopathies, including AD, that were shown to behave like seeds, accelerating tau pathology and tangle formation in predisposed mice. More specifically, in vivo data suggest that brain …lysates from mice harboring the P301S mutation of tau can seed protein aggregation when injected into the hippocampi of human wild-type tau transgenic ALZ17 mice. Here, we compared the seeding potential of lysates and extracellular vesicles enriched for exosomes (EVs) from wild-type and human P301L tau transgenic rTg4510 mouse brains. We show that transgenic EVs cause increased tau phosphorylation and soluble oligomer formation in a manner comparable to that of freely available proteins in brain lysates, a prerequisite for the formation of mature protein aggregates. Show more

Keywords: Alzheimer’s disease, extracellular vesicles, phosphorylation, seeding, tau

DOI: 10.3233/JAD-160371

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1207-1217, 2016

Authors: Boehm-Cagan, Anat | Bar, Roni | Liraz, Ori | Bielicki, John K. | Johansson, Jan O. | Michaelson, Daniel M.

Article Type: Research Article

Abstract: The allele ɛ4 of apolipoprotein E (apoE4) is the most prevalent genetic risk factor for Alzheimer’s disease (AD) and is therefore a promising therapeutic target. Human and animal model studies suggest that apoE4 is hypolipidated; accordingly, we have previously shown that the retinoid X receptor (RXR) agonist bexarotene upregulates ABCA1, the main apoE-lipidating protein, resulting in increased lipidation of apoE4, and the subsequent reversal of the pathological effects of apoE4, namely: accumulation of Aβ42 and hyperphosphorylated tau, as well as reduction in the levels of synaptic markers and cognitive deficits. Since the RXR system has numerous other targets, it …is important to devise the means of activating ABCA1 selectively. We presently utilized CS-6253, a peptide shown to directly activate ABCA1 in vitro , and examined the extent to which it can affect the degree of lipidation of apoE4 in vivo and counteract the associated brain and behavioral pathologies. This revealed that treatment of young apoE4-targeted replacement mice with CS-6253 increases the lipidation of apoE4. This was associated with a reversal of the apoE4-driven Aβ42 accumulation and tau hyperphosphorylation in hippocampal neurons, as well as of the synaptic impairments and cognitive deficits. These findings suggest that the pathological effects of apoE4 in vivo are associated with decreased activation of ABCA1 and impaired lipidation of apoE4 and that the downstream brain-related pathology and cognitive deficits can be counteracted by treatment with the ABCA1 agonist CS-6253. These findings have important clinical ramifications and put forward ABCA1 as a promising target for apoE4-related treatment of AD. Show more

Keywords: ABCA1, Alzheimer’s disease, apoE, CS-6253, lipidation, lipids

DOI: 10.3233/JAD-160467

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1219-1233, 2016

Authors: Sepe-Monti, Micaela | Vanacore, Nicola | Bartorelli, Luisa | Tognetti, Alessandra | Giubilei, Franco | Caregiver Study Group Savvy

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a major cause of disability in the elderly, leading to a considerable burden on caregivers and high costs to society. Psycho-education programs such as the Savvy Caregiver Program (SCP) are reported to be a successful means of reducing caregivers’ distress through various intervention strategies. The aim of the present study was to assess the efficacy of the SCP in reducing the burden and psychological symptoms in caregivers of AD patients and to analyze the coping strategies adopted by the caregivers. The study was designed as a multicenter, randomized, controlled, pilot clinical trial. One hundred and sixty-four …caregivers of patients with probable AD were randomized. The SCP was structured in six, weekly, two-hour sessions. All the clinical scales were administered before treatment, two weeks and six months after treatment. Caregivers in the SCP group displayed better coping strategies adopted to positive attitudes, and they tended to be less anxious and less depressed than those in the control group. However, caregiver burden levels were not reduced in SCP caregivers. The patients of SCP caregivers received a lower number of new prescriptions of neuroleptics during the 6 months of follow-up than the patients of control caregivers and apathy was the neuropsychiatric symptom that improved most as a result of the SCP. The results of this study suggest that the SCP may improve coping strategies of caregivers of people affected by AD, influencing their psychological symptoms and those of their patients. Show more

Keywords: Alzheimer’s disease, caregivers, coping skills, dementia

DOI: 10.3233/JAD-160235

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1235-1246, 2016

Article Type: Book Review

DOI: 10.3233/JAD-160816

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1247-1248, 2016

Authors: Dugger, Brittany N. | Whiteside, Charisse M. | Maarouf, Chera L. | Walker, Douglas G. | Beach, Thomas G. | Sue, Lucia I. | Garcia, Angelica | Dunckley, Travis | Meechoovet, Bessie | Reiman, Eric M. | Roher, Alex E.

Article Type: Correction

DOI: 10.3233/JAD-169007

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1249-1249, 2016

Authors: Tanifum, Eric A. | Ghaghada, Ketan | Vollert, Craig | Head, Elizabeth | Eriksen, Jason L.

Article Type: Correction

DOI: 10.3233/JAD-169008

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1251-1251, 2016

Article Type: Other

DOI: 10.3233/JAD-160749

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1253-1257, 2016