Journal of Alzheimer's Disease - Volume 60, issue 2

Authors: Kuate-Tegueu, Callixte | Avila-Funes, José-Alberto | Simo, Nadine | Le Goff, Mélanie | Amiéva, Hélène | Dartigues, Jean-François | Tabue-Teguo, Maturin

Article Type: Research Article

Abstract: Background: Gait speed (GS) and psychomotor speed (PS) could be considered as two different dimensions of age-related slowness and both measures are associated with higher risk of adverse health-related outcomes among elderly people. Objective: To determine the association between GS, PS, and incident dementia among community-dwelling older adults. Methods: Twelve-year longitudinal study of 1,265 participants in the Bordeaux Three-City Study, a French prospective cohort designed to determine the risk of dementia and cognitive impairment attributable to cardiovascular risk factors. Participants completed a battery of cognitive tests, including time to complete the Trail Making Test A, and …a walking speed test. The incidence of dementia was determined over the 12-year follow-up period. Cox proportional hazards models with delayed entry were used to estimate the cumulative risk of dementia and were adjusted for sex, education, and ApoE4 genotype. Results: Mean age of participants was 74.0 years (SD 4.8). Over the 12-year follow-up, 203 participants developed dementia. GS and PS were both independent predictors of incident all-cause dementia after 12 years of follow-up. For a one SD increase of either GS or PS, the hazard ratio (HR) for Alzheimer’s disease was 1.2 (95% CI = 1.02–1.32) and 1.4 (95% CI = 1.2–1.61), respectively; whereas for incident vascular dementia, the HR was 1.3 (95% CI = 1.05–1.71) and 1.5 (95% CI = 1.16–2.08), respectively. No significant interaction between GS and PS was observed. Conclusions: In older French people aged 65+, our findings showed that both low GS and PS were independently associated with risk of incident Alzheimer’s disease and vascular dementia. Show more

Keywords: Dementia, elderly, epidemiology, gait speed, psychomotor speed, vascular process

DOI: 10.3233/JAD-170267

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 585-592, 2017

Authors: Mavroeidi, Panagiota | Mavrofrydi, Olga | Pappa, Elpiniki | Panopoulou, Myrto | Papazafiri, Panagiota | Haralambous, Sylva | Efthimiopoulos, Spiros

Article Type: Research Article

Abstract: Alterations in tau synaptic distribution are considered to underlie synaptic dysfunction observed in Alzheimer’s disease (AD). In the present study, brain blood hypoperfusion was simulated in mouse brain slices, and tau levels and phosphorylation were investigated in total extracts, as well as in postsynaptic density fractions (PSDs) and non-PSDs obtained through differential extraction and centrifugation. Oxygen deprivation (OD) resulted in tau dephosphorylation at several AD-related residues and activation of GSK3β and phosphatase PP2A. On the contrary, glucose deprivation (GD) did not affect total levels of cellular tau or its phosphorylation despite inactivation of GSK3β. However, tau distribution in PSD and …non-PSD fractions and the pattern of tau phosphorylation in these compartments is highly complex. In PSDs, tau was increased under GD conditions and decreased under OD conditions. GD resulted in tau dephosphorylation at Ser199, Ser262, and Ser396 while OD resulted in tau hyperphosphorylation at Ser199 and Ser404. In the non-PSD fraction, GD or OD resulted in lower levels of tau, but the phosphorylation status of tau was differentially affected. In GD conditions, tau was found dephosphorylated at Ser199, Thr205, and Ser404 and hyperphosphorylated at Ser262. However, in OD conditions tau was found hyperphosphorylated at Thr205, SerSer356, Ser396, and Ser404. Combined OD and GD resulted in degradation of cellular tau and dephosphorylation of PSD tau at Ser396 and Ser404. These results indicate that oxygen deprivation causes dephosphorylation of tau, while GD and OD differentially affect distribution of total tau and tau phosphorylation variants in neuronal compartments by activating different mechanisms. Show more

Keywords: Alzheimer’s disease, glucose deprivation, oxygen deprivation, postsynaptic density, tau distribution, tau phosphorylation

DOI: 10.3233/JAD-170157

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 593-604, 2017

Authors: Amen, Daniel G. | Trujillo, Manuel | Keator, David | Taylor, Derek V. | Willeumier, Kristen | Meysami, Somayeh | Raji, Cyrus A.

Article Type: Research Article

Abstract: Background: Studies have reported that females have widespread increases in regional cerebral blood flow, but the studies were relatively small and inconsistent. Objective: Here we analyzed a healthy and a very large clinical psychiatric population to determine the effect of gender, using single photon emission computed tomography (SPECT). Methods: Whole brain and region of interest (ROI) gender differences were analyzed in a total of 46,034 SPECT scans at baseline and concentration. The sample included 119 healthy subjects and 26,683 patients (60.4% male, 39.6% female); a subset of 11,587 patients had complete diagnostic information. A total of …128 regions were analyzed according to the AAL Atlas, using ROI Extract and SPSS statistical software programs, controlling for age, diagnoses, and correcting for multiple comparisons. Results: Compared to males, healthy females showed significant whole brain (p  < 0.01) and ROI increases in 65 baseline and 48 concentration regions (p  < 0.01 corrected). Healthy males showed non-significant increases in 9 and 22 regions, respectively. In the clinical group, there were widespread significant increases in females, especially in the prefrontal and limbic regions, and specific increases in males in the inferior occipital lobes, inferior temporal lobes, and lobule 7 and Crus 2 of the cerebellum. These findings were replicated in the subset of 11,587 patients with the effect of diagnoses removed. Conclusions: Our results demonstrated significant gender differences in a healthy and clinical population. Understanding these differences is crucial in evaluating functional neuroimaging and may be useful in understanding the epidemiological gender differences among psychiatric disorders. Show more

Keywords: Brain, gender, regions of interest, SPECT

DOI: 10.3233/JAD-170432

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 605-614, 2017

Authors: Pantoni, Leonardo | Poggesi, Anna | Diciotti, Stefano | Valenti, Raffaella | Orsolini, Stefano | Della Rocca, Eleonora | Inzitari, Domenico | Mascalchi, Mario | Salvadori, Emilia

Article Type: Research Article

Abstract: Background and Objective: Mild cognitive impairment (MCI) patients with small vessel disease (SVD) are at high dementia risk. We tested the effects of cognitive rehabilitation in these patients using the Attention Process Training-II (APT-II) program in a single-blinded, randomized clinical trial. Methods: Patients were randomized to APT-II or standard care and evaluated at baseline, 6, and 12 months with functional, quality of life, cognitive tests, and resting state functional MRI (rsfMRI). Results: Forty-six patients were enrolled and 43 (mean±SD age 75.1±6.8) completed the study. No change was seen in functionality and quality of life between treated …and non-treated patients. However, the Rey Auditory-Verbal Learning Test immediate recall showed a significant improvement in treated compared to non-treated group (change score 6 versus 12 months: 1.8±4.9 and –1.4±3.8, p  = 0.021; baseline versus 12 months: 3.8±6.1 and 0.2±4.4, p  = 0.032). A higher proportion of treated patients had stable/better evaluation compared to non-treated group on Visual search test (6 versus 12 months: 95% versus 71%, p  = 0.038) and Rey–Osterrieth Complex Figure copy (6 versus 12 months: 95% versus 67%, p  = 0.027). RsfMRI, performed in a subsample, showed that the difference between follow-up and baseline in synchronization of activity in cerebellar areas was significantly greater in treated than in non-treated patients. Conclusion: We were unable to show a significant effect in quality of life or functional status in treated patients with MCI and SVD. However, APT-II produces some beneficial effects in focused attention and working memory and seems to increase activity in brain circuits involved in cognitive processes. Show more

Keywords: Cerebrovascular disorders, clinical trial, cognitive dysfunction, functional magnetic resonance imaging, rehabilitation

DOI: 10.3233/JAD-170428

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 615-624, 2017

Authors: Chung, Chih-Ping | Lee, Hsiang-Ying | Lin, Po-Chen | Wang, Pei-Ning

Article Type: Research Article

Abstract: The concept that excess pulsation in cerebral arteries might be involved at the early stage of dementia is based on the results of studies on aorta stiffness. In these studies, aorta stiffness is cross-sectionally associated with cognitive impairment and longitudinally related to cognitive decline in non-demented subjects. However, a direct measure of cerebral artery pulsatility is absent in the literature. We aimed to investigate the associations between cerebral artery pulsatility and (1) different cognitive-domains and (2) conversion to dementia in non-demented individuals at the prodromal-stage of Alzheimer’s disease (AD). Non-demented individuals with subjective memory decline or mild cognitive impairment were …included. Neuropsychological tests at baseline and cognitive status at 6 years were evaluated. Cerebral pulsatility was assessed in the middle cerebral artery (MCA) and posterior cerebral artery by transcranial color-coded sonography. Multivariate-analyses of 79 subjects with robust acoustic windows showed that increased pulsatility in cerebral arteries was significantly associated with impairment in corresponding cognitive domains. Analyses in 54 subjects who completed 6-year follow up revealed that high left MCA pulsation (pulsatility index≥1.1) independently predicted conversion to AD with an odds-ratio of 11.2. Our results demonstrate the spatio-temporal relationship between increased cerebral artery pulsation and cognitive impairment and suggest that increased cerebrovascular pulsation might be involved in the early pathogenesis of AD. Cerebrovascular pulsation may be a therapeutic target to prevent/delay AD onset. Future studies with other AD biomarkers and animal/cell models of increased vascular-pulsation are needed to elucidate the mechanisms by which cerebrovascular pulsatile injury initiates or precipitates neurodegeneration in AD. Show more

Keywords: Alzheimer’s disease, cerebral artery, cognitive function, pulsatility index

DOI: 10.3233/JAD-170349

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 625-632, 2017

Authors: Cid-Fernández, Susana | Lindín, Mónica | Díaz, Fernando

Article Type: Research Article

Abstract: Early identification of amnestic mild cognitive impairment (aMCI) subtypes is important for early diagnosis and prognosis of Alzheimer’s disease. Healthy, single-domain (sdaMCI) and multiple-domain aMCI (mdaMCI) participants performed an auditory-visual distraction-attention task. Event-related brain potentials (ERPs) were recorded while the participants performed the task to evaluate Go/NoGo N2 and P3 ERP components. The results showed the expected behavioral and cognitive decline in mdaMCI participants relative to controls (fewer hits, longer reaction times [RTs], slightly smaller Go-N2 and NoGo-N2 amplitudes), while sdaMCI participants showed some decline (slightly longer RTs, smaller Go- and NoGo-N2 amplitudes) along with some unexpected results (a late …positive slow wave, PSW) and good levels of execution. In addition, some of these parameters proved to be useful markers. Thus, the number of hits was the best marker for diagnosing mdaMCI participants (distinguishing them from controls, from sdaMCI participants, and from both groups together), while the PSW amplitude was the best marker for diagnosing sdaMCI participants (distinguishing them from controls, and from control & mdaMCI participants). Show more

Keywords: Biomarkers, electroencephalogram, event-related potentials, mild cognitive impairment, slow wave

DOI: 10.3233/JAD-170369

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 633-649, 2017

Authors: Antón-Fernández, Alejandro | Merchán-Rubira, Jesús | Avila, Jesús | Hernández, Félix | DeFelipe, Javier | Muñoz, Alberto

Article Type: Research Article

Abstract: The Golgi apparatus (GA) is a highly dynamic organelle involved in the processing and sorting of cellular proteins. In Alzheimer’s disease (AD), it has been shown to decrease in size and become fragmented in neocortical and hippocampal neuronal subpopulations. This fragmentation and decrease in size of the GA in AD has been related to the accumulation of hyperphosphorylated tau. However, the involvement of other pathological factors associated with the course of the disease, such as the extracellular accumulation of amyloid-β (Aβ) aggregates, cannot be ruled out, since both pathologies are present in AD patients. Here we use the P301S tauopathy …mouse model to examine possible alterations of the GA in neurons that overexpress human tau (P301S mutated gene) in neocortical and hippocampal neurons, using double immunofluorescence techniques and confocal microscopy. Quantitative analysis revealed that neurofibrillary tangle (NFT)-bearing neurons had important morphological alterations and reductions in the surface area and volume of the GA compared with NFT-free neurons. Since in this mouse model there are no Aβ aggregates typical of AD, the present findings support the idea that the progressive accumulation of phospho-tau is associated with structural alterations of the GA, and that these changes may occur in the absence of Aβ pathology. Show more

Keywords: Golgi apparatus, hippocampus, neocortex, neurofibrillary tangles, tauopathies

DOI: 10.3233/JAD-170332

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 651-661, 2017

Authors: Pongan, Elodie | Tillmann, Barbara | Leveque, Yohana | Trombert, Béatrice | Getenet, Jean Claude | Auguste, Nicolas | Dauphinot, Virginie | El Haouari, Hanane | Navez, Malou | Dorey, Jean-Michel | Krolak-Salmon, Pierre | The LACMé Group | Laurent, Bernard | Rouch, Isabelle

Collaborators: Auguste, Nicolas | Bachelet, Romain | Brunon, Laurence | Dayot, Jenny | Dorey, Jean-Michel | El Haouari, Hanane | Fatisson, Marion | Ferrer, Marion | Gaillat, Charlotte | Gentil, Claire | Getenet, Jean Claude | Goldet, Karine | Krolak-Salmon, Pierre | Laurent, Bernard | Leroyer, Marie | Leveque, Yohana | Michon, Agnès | Mortreux, Angélique | Navez, Malou | Neagu, Anca | Perrot, Catherine | Pongan, Elodie | Rouch, Isabelle | Solimeo, Mathilde | Tillmann, Barbara | Touzet du Vigier, Anaïs | Vulliez, Elodie

Article Type: Research Article

Abstract: Background: Among non-pharmacological therapies, musical intervention is often used for patients with Alzheimer’s disease (AD) and patients presenting chronic pain. However, their efficacy is still under debate. Objective: Our aim was to determine the efficacy of choral singing versus painting sessions on chronic pain, mood, quality of life, and cognition in AD patients. Methods: In this multicenter randomized controlled trial, 59 mild AD patients were randomized to a 12-week singing (SG; n  = 31) or painting group (PG; n  = 28). Chronic pain, anxiety, depression, and quality of life were assessed before, after, and 1 month after the …sessions. Cognitive abilities were assessed before and after interventions. The evolution of these different measures was assessed with mixed linear models. The primary data analysis was by intention-to-treat, and completed by a ‘per protocol’ approach. Results: Both singing and painting interventions led to significant pain reduction (Time effect: F = 4.71; p  = 0.01), reduced anxiety (Time effect: F = 10.74; p  < 0.0001), improved Quality of Life (Time effect: F = 6.79; p  = 0.002), improved digit span (F = 12.93; p  = 0.001), and inhibitory processes (Time effect: F = 4.93; p  = 0.03). Depression was reduced over time in PG only (Time x Group effect: F = 4.53; p  = 0.01). Verbal Memory performance remained stable over time in SG, but decreased in PG (Time x group effect: F = 9.29; p  = 0.004). Conclusion: Findings suggest that singing and painting interventions may reduce pain and improve mood, quality of life, and cognition in patients with mild AD, with differential effects of painting for depression and singing for memory performance. Show more

Keywords: Alzheimer’s disease, anxiety, cognitive impairment, depression, music, pain

DOI: 10.3233/JAD-170410

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 663-677, 2017

Authors: Tao, Wuhai | Li, Xin | Zhang, Junying | Chen, Yaojing | Ma, Chao | Liu, Zhen | Yang, Caishui | Wang, Wenxiao | Chen, Kewei | Wang, Jun | Zhang, Zhanjun

Article Type: Research Article

Abstract: The alteration of the default mode network (DMN) functional connectivity (FC) has been reported in patients with amnestic mild cognitive impairment (aMCI) as a predictor of Alzheimer’s disease (AD). However, no studies exist that examined stage-dependent DMN FC changes throughout the course of aMCI. The present study aims to characterize patterns of DMN FC over three aMCI stages as first defined. Utilizing the extreme groups approach on the performance of memory tasks, aMCI subjects were divided into mild, moderate, and severe stages. Independent component analysis was used to assess DMN for individual patients in each of the three cross-sectionally defined …stages. Instead of finding that continued monotonic decline was the case for the hippocampus volume, which we also investigated in this study, we observed an increase in DMN functional connectivity from mild aMCI to moderate aMCI and a decrease to severe aMCI, mainly in the left precuneus and superior parietal lobe. Moreover, the FC was significantly associated with cognitive performance. Though a longitudinal study is needed to confirm these results, our cross-sectional finding is that non-linear FC changes in DMN could be a characteristic of prodromal early disease development. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, default mode network, functional connectivity, non-monotomic trajectory

DOI: 10.3233/JAD-170252

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 679-690, 2017

Authors: Larsson, Susanna C. | Traylor, Matthew | Burgess, Stephen | Markus, Hugh S.

Article Type: Research Article

Abstract: Background: Observational studies have linked increased adult height with better cognitive performance and reduced risk of Alzheimer’s disease (AD). It is unclear whether the associations are due to shared biological processes that influence height and AD or due to confounding by early life exposures or environmental factors. Objective: To use a genetic approach to investigate the association between adult height and AD. Methods: We selected 682 single nucleotide polymorphisms (SNPs) associated with height at genome-wide significance (p  < 5×10–8 ) in the Genetic Investigation of ANthropometric Traits (GIANT) consortium. Summary statistics for each of these SNPs on …AD were obtained from the International Genomics of Alzheimer’s Project (IGAP) of 17,008 individuals with AD and 37,154 controls. The estimate of the association between genetically predicted height and AD was calculated using the inverse-variance weighted method. Results: The odds ratio of AD was 0.91 (95% confidence interval, 0.86–0.95; p  = 9.8×10–5 ) per one standard deviation increase (about 6.5 cm) in genetically predicted height based on 682 SNPs, which were clustered in 419 loci. In an analysis restricted to one SNP from each height-associated locus (n  = 419 SNPs), the corresponding OR was 0.92 (95% confidence interval, 0.86–0.97; p  = 4.8×10–3 ). Conclusions: This finding suggests that biological processes that influence adult height may have a role in the etiology of AD. Show more

Keywords: Alzheimer’s disease, anthropometry, genetics, polymorphism, single nucleotide

DOI: 10.3233/JAD-170528

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 691-698, 2017

Authors: Kueider, Alexandra M. | An, Yang | Tanaka, Toshiko | Kitner-Triolo, Melissa H. | Studenski, Stephanie | Ferrucci, Luigi | Thambisetty, Madhav

Article Type: Research Article

Abstract: Serum uric acid (SUA) is an abundant natural antioxidant capable of reducing cellular oxidation, a major cause of neurodegenerative disease. In line with this, SUA levels are lower in Alzheimer’s disease; however, the association between SUA and cognition remains unclear. Results from studies examining the effects of SUA on cognition may be difficult to interpret in the context of normal versus pathological aging. This study examined sex-specific associations of baseline SUA with cognition during aging. Data from dementia-free participants initially aged 26–99 (N  = 1,451) recruited for the Baltimore Longitudinal Study of Aging (BLSA), were used in the current analyses. SUA …was assessed using blood samples collected during research visits. Cognition was measured using five composite scores (verbal memory, attention, executive function, language, and visuospatial ability). At the first study visit, compared with women, men were older, more likely to be White, had more years of education, higher baseline SUA levels, and higher cardiovascular risk scores. Higher baseline SUA was associated with attenuated declines in attention (β= 0.006; p  = 0.03) and visuospatial abilities (β= 0.007; p  = 0.01) in men. There was a trend to suggest higher baseline SUA in men was associated with attenuated declines in language, but this finding did not reach statistical significance (p  = 0.09). There were no significant findings with SUA and cognition in women. In this sample of cognitively healthy, community-dwelling adults, we found that higher SUA levels at baseline were associated with attenuated declines in attention and visuospatial abilities in men. SUA was not associated with cognition or change in cognition over time in women. Show more

Keywords: Aging, cognitive function, older adults, uric acid

DOI: 10.3233/JAD-170287

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 699-706, 2017

Authors: Weissberger, Gali H. | Melrose, Rebecca J. | Fanale, Candace M. | Veliz, Joseph V. | Sultzer, David L.

Article Type: Research Article

Abstract: Orientation to time, date, and place is commonly utilized in clinical settings to aid in diagnosis, staging, and monitoring of Alzheimer’s disease (AD). This study aimed to identify the cerebral metabolic correlates of orientation in patients with AD, and the degree to which regions associated with orientation overlap with memory-related structures. Eighty-five patients with a diagnosis of probable AD underwent fluorodeoxyglucose positron emission tomography (FDG-PET) and neuropsychological testing. Orientation items from the Dementia Rating Scale and recognition performance from the Consortium to Establish a Registry for AD (CERAD) Word List Learning test were correlated with cerebral glucose metabolism. Post-hoc …analyses examined neuropsychological predictors of orientation. Better orientation performance related to greater cerebral metabolism in the bilateral middle-inferior temporal lobes, bilateral middle-posterior cingulate, left angular gyrus, and left middle occipital gyrus. In comparison, higher CERAD recognition discriminability score was associated with greater metabolic activity in left medial temporal lobe regions including the hippocampal and parahippocampal gyri, and the left fusiform gyrus. Post-hoc behavioral analyses revealed multiple cognitive functions to be related to orientation, including list learning, recognition memory, visuospatial functioning, attention, and language. Findings from the present study suggest that disorientation in AD results from dysfunction of a network of structures and cognitive abilities commonly found to be implicated in AD. The study supports the notion that memory is necessary but not sufficient for successful orientation. Show more

Keywords: Alzheimer’s disease, fluorodeoxyglucose F18, memory, neuropsychology, orientation

DOI: 10.3233/JAD-170420

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 707-719, 2017

Authors: Karki, Reagon | Kodamullil, Alpha Tom | Hofmann-Apitius, Martin

Article Type: Research Article

Abstract: Background: Various studies suggest a comorbid association between Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) indicating that there could be shared underlying pathophysiological mechanisms. Objective: This study aims to systematically model relevant knowledge at the molecular level to find a mechanistic rationale explaining the existing comorbid association between AD and T2DM. Method: We have used a knowledge-based modeling approach to build two network models for AD and T2DM using Biological Expression Language (BEL), which is capable of capturing and representing causal and correlative relationships at both molecular and clinical levels from various knowledge resources. …Results: Using comparative analysis, we have identified several putative “shared pathways”. We demonstrate, at a mechanistic level, how the insulin signaling pathway is related to other significant AD pathways such as the neurotrophin signaling pathway, PI3K/AKT signaling, MTOR signaling, and MAPK signaling and how these pathways do cross-talk with each other both in AD and T2DM. In addition, we present a mechanistic hypothesis that explains both favorable and adverse effects of the anti-diabetic drug metformin in AD. Conclusion: The two computable models introduced here provide a powerful framework to identify plausible mechanistic links shared between AD and T2DM and thereby identify targeted pathways for new therapeutics. Our approach can also be used to provide mechanistic answers to the question of why some T2DM treatments seem to increase the risk of AD. Show more

Keywords: Alzheimer’s disease, comorbidity, disease mechanisms, disease modeling, metformin, OpenBEL, type 2 diabetes mellitus

DOI: 10.3233/JAD-170440

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 721-731, 2017

Authors: Zhang, Li | Sun, Caixian | Jin, Yaxi | Gao, Kai | Shi, Xudong | Qiu, Wenying | Ma, Chao | Zhang, Lianfeng

Article Type: Research Article

Abstract: Dysfunctional Wnt signaling is associated with Alzheimer’s disease (AD), and activation of the Wnt signaling pathway inhibits AD development. Dickkopf 3 (Dkk3) is a modulator of the Wnt signaling pathway and is physiologically expressed in the brain. The role of Dkk3 in the pathogenesis of AD has not been evaluated. In the present study, we determined that Dkk3 expression was significantly decreased in brain tissue from AD patients and the AD transgenic mouse model APPswe/PS1dE9 (AD mice). Transgenic mice with brain tissue-specific Dkk3 expression were generated or crossed with AD mice to study the effects of Dkk3 on AD. In …AD mice, transgenic expression of Dkk3 improved abnormalities in learning, memory, and locomotor activity, reduced the accumulation of amyloid-β, and ameliorated glucose uptake deficits. Furthermore, we determined that Dkk3 downregulated GSK-3β, a central negative regulator in canonical Wnt signaling, and upregulated PKCβ1, a factor implicated in noncanonical Wnt signaling. This indicates that increased activation of GSK-3β and the inhibition of PKCβ1 in AD patients may be responsible for the dysfunctional Wnt signaling in AD. In summary, our data suggest that Dkk3 is an agonist of Wnt signaling, and the ability of transgenic expression of Dkk3 to compensate for the decrease in Dkk3 expression in AD mice, reverse dysfunctional Wnt signaling, and partially inhibit the pathological development of AD suggests that Dkk3 could serve as a therapeutic target for the treatment of AD. Show more

Keywords: Alzheimer’s disease, cognition, Dkk3, transgenic mice, Wnt signaling pathway

DOI: 10.3233/JAD-161254

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 733-746, 2017