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• Editorial

  Pathological trajectory in the Ts65Dn model of Down syndrome

  Relevance score: 10.927786

  Savannah Tallino, Wendy Winslow, Ramon Velazquez

  Keywords: Down syndrome, Ts65Dn, amyloid-beta, cholinergic

  Published in Aging on January 20, 2023

• Research Paper Volume 12, Issue 21 pp 22266-22290

  Cholesterol-rich naked mole-rat brain lipid membranes are susceptible to amyloid beta-induced damage in vitro

  Relevance score: 11.042842

  Daniel Frankel, Matthew Davies, Bharat Bhushan, Yavuz Kulaberoglu, Paulina Urriola-Munoz, Justine Bertrand-Michel, Melissa R. Pergande, Andrew A. Smith, Swapan Preet, Thomas J. Park, Michele Vendruscolo, Kenneth S. Rankin, Stephanie M. Cologna, Janet R. Kumita, Nicolas Cenac, Ewan St John Smith

  Keywords: Naked mole-rat, neurodegeneration, amyloid beta, brain, lipidomics

  Published in Aging on November 4, 2020

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  Naked mole-rats are extraordinarily long-lived rodents that offer unique opportunities to study the molecular origins of age-related neurodegenerative diseases. Remarkably, they do not accumulate amyloid plaques, even though their brains contain high concentrations of amyloid beta (Aβ) peptide from a young age. Therefore, they represent a particularly favourable organism to study the mechanisms of resistance against Aβ neurotoxicity. Here we examine the composition, phase behaviour, and Aβ interactions of naked mole-rat brain lipids. Relative to mouse, naked mole-rat brain lipids are rich in cholesterol and contain sphingomyelin in lower amounts and of shorter chain lengths. Proteins associated with the metabolism of ceramides, sphingomyelins and sphingosine-1-phosphate receptor 1 were also found to be decreased in naked mole-rat brain lysates. Correspondingly, we find that naked mole-rat brain lipid membranes exhibit a high degree of phase separation, with the liquid ordered phase extending to 80% of the supported lipid bilayer. These observations are consistent with the ‘membrane pacemaker’ hypothesis of ageing, according to which long-living species have lipid membranes particularly resistant to oxidative damage. We also found that exposure to Aβ disrupts naked mole-rat brain lipid membranes significantly, breaking the membrane into pieces while mouse brain derived lipids remain largely intact upon Aβ exposure.

• Research Paper Volume 11, Issue 24 pp 12202-12212

  Cerebrospinal fluid and blood Aβ levels in Down syndrome patients with and without dementia: a meta-analysis study

  Relevance score: 9.889526

  Yang Du, Lei Chen, Yuguo Jiao, Yong Cheng

  Keywords: dementia, Down syndrome, amyloid beta, cerebrospinal fluid, blood

  Published in Aging on December 20, 2019

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  Abnormal β-amyloid (Aβ) levels were found in patients with Down syndrome (DS). However, Aβ levels in patients with DS and DS with dementia (DSD) vary considerably across studies. Therefore, we performed a systematic literature review and quantitatively summarized the clinical Aβ data on the cerebrospinal fluid (CSF) and blood of patients with DS and those with DSD using a meta-analytical technique. We performed a systematic search of the PubMed and Web of Science and identified 27 studies for inclusion in the meta-analysis. Random-effects meta-analysis indicated that the levels of blood Aβ_1-40 and Aβ_1-42 were significantly elevated in patients with DS compared with those in healthy control (HC) subjects. In contrast, there were no significant differences between patients with DS and those with DSD in the blood Aβ_1-40 and Aβ_1-42 levels. The CSF Aβ_1-42 levels were significantly decreased in patients with DS compared to those in HC subjects. Further, CSF Aβ_1-42 levels were significantly decreased in patients with DSD compared to those with DS, with a large effect size. Taken together, our results demonstrated that blood Aβ_1-40 and Aβ_1-42 levels were significantly increased in patients with DS while CSF Aβ_1-42, but not Aβ_1-40 levels were significantly decreased in patients with DS.

  

  PRISMA flowchart of the literature search.

  
  
  

  

  Forest plot for random-effects meta-analysis on difference in blood Aβ_1-40 (A) and Aβ_1-42 (B) concentrations between DS patients and HC subjects; blood Aβ_1-40 (C) and Aβ_1-42 (D) concentrations between DSD and DS patients. DS, Down syndrome. DSD, Down syndrome with dementia. HC, healthy control. CI, confidence interval.

  
  
  

  

  Forest plot for random-effects meta-analysis on difference in CSF Aβ_1-40 (A) and Aβ_1-42 (B) concentrations between DS patients and HC subjects; CSF Aβ_1-40 (C) and Aβ_1-42 (D) concentrations between DSD and DS patients. CSF, Cerebrospinal fluid. DS, Down syndrome. DSD, Down syndrome with dementia. HC, healthy control. CI, confidence interval.

  
  
  

  

  Visual inspection of funnel plots suggested no significant publication bias among studies comparing (A) blood Aβ1-40 and (B) Aβ1-42 levels between DS patients and HC subjects.

  
  
  

• Research Paper Volume 11, Issue 22 pp 10242-10251

  Studies on APP metabolism related to age-associated mitochondrial dysfunction in APP/PS1 transgenic mice

  Relevance score: 8.944279

  Lizhi Chen, Shicheng Xu, Tong Wu, Yijia Shao, Li Luo, Lingqi Zhou, Shanshan Ou, Hai Tang, Wenhua Huang, Kaihua Guo, Jie Xu

  Keywords: mitochondria dysfunction, adenosine 5’-triphosphate, Amyloid-beta, platelets, APP/PS1 mice

  Published in Aging on November 19, 2019

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  The aging brain with mitochondrial dysfunction and a reduced adenosine 5’-triphosphate (ATP) has been implicated in the onset and progression of β-Amyloid (Aβ)-induced neuronal toxicity in AD. To unravel the function of ATP and the underlying mechanisms on AD development, APP/PS1 double transgenic mice and wild-type (WT) C57 mice at 6 and 10 months of age were studied. We demonstrated a decreased ATP release in the hippocampus and platelet of APP/PS1 mice, comparing to C57 mice at a relatively early age. Levels of Aβ were raised in both hippocampus and platelet of APP/PS1 mice, accompanied by a decrease of α-secretase activity and an increase of β-secretase activity. Moreover, our results presented an age-dependent rise in mitochondrial vulnerability to oxidation in APP/PS1 mice. In addition, we found decreased pSer473-Akt levels, increased GSK3β activity by inhibiting phosphorylation at Ser9 in aged APP/PS1 mice and these dysfunctions probably due to down-regulation of Bcl-2 and up-regulation of cleaved caspase-3. Therefore, we demonstrate that PI3K/Akt/GSK3β signaling pathway could be involved in Aβ-associated mitochondrial dysfunction of APP/PS1 mice and APP abnormal metabolism in platelet might provide potential biomarkers for early diagnosis of AD.

  

  Hippocampal and platelets ATP content in and from APP/PS1 transgenic mice and C57 mice. (A) ATP content in hippocampi; (B) ATP content in platelets. Results are expressed as a mean ± SD value of six experiments measured in duplicate. The values are expressed as percentage of control, which is set to 100%. ^**P < 0.01 vs. C57 (6 months), ^##P < 0.01 vs. APP/PS1 (6 months), ⁺⁺P < 0.01 vs. C57 (10 months).

  
  
  

  

  Aβ1-40 and Aβ1-42 levels in hippocampus and platelets from APP/PS1 transgenic mice and C57 mice. (A) Aβ1-40 levels in hippocampus; (B) Aβ1-42 levels in hippocampus; (C) Aβ1-40 levels in platelets; (D) Aβ1-42 levels in platelets. Values are expressed as mean ± SD of six experiments measured in duplicate. ^**P < 0.01 vs. C57 (6 months), ^##P < 0.01 vs. APP/PS1 (6 months), ⁺⁺P < 0.01 vs. C57 (10 months).

  
  
  

  

  Scatter plots of the correlation between hippocampal and platelet Aβ variables in APP/PS1 transgenic mice and C57 mice. (A) The correlation analysis between hippocampal Aβ1-40 and platelet Aβ1-40 at 6 and 10 months. (B) The correlation analysis between hippocampal Aβ1-42 and platelet Aβ1-42 at 6 and 10months.

  
  
  

  

  Activities of α- (A) and β-secretase (B) in platelets of APP/PS1 transgenic mice and C57 mice. ^**P < 0.01 vs. C57 (6 months), ^##P < 0.01 vs. APP/PS1 (6 months), ⁺⁺P < 0.01 vs. C57 (10 months).

  
  
  

  

  Western blot analysis for p-Akt, p-GSK3β, Bcl-2 and Cleaved caspase-3 in the platelets of APP/PS1 transgenic mice and C57 mice. Band intensities were quantified using Image J software. Each value was calculated on the basis of the data obtained from three independent experiment. Representative bar diagram showing quantitative results for relative levels of (B) p-Akt, (C) p-GSK3β, (D) Bcl-2, (E) Cleaved caspase-3. ^*P < 0.05 vs. C57 (6 months), ^**P < 0.01 vs. C57 (6 months), ^##P < 0.01 vs. APP/PS1 (6 months), ⁺P < 0.05 vs. C57 (10 months), ⁺⁺P < 0.01 vs. C57 (10 months).

  
  
  

  

  Schematic representation of the potential mechanisms involved in Aβ-associated mitochondrial dysfunction in APP/PS1 mice. In the presence of Aβ, mitochondrial dysfunction has been shown to be associated with mitochondrial ATP production and cell signaling cascades, eventually leading to apoptosis. The red and blue arrows visualize the increased or decreased processes of APP/PS1 mice proteins compared to the control C57 mice, respectively.

  
  
  

  

  Research protocol. (A) An overview of the experimental scheme. (B) Graphic illustrating the platelet preparation from the tube-method protocol. The extraction of a small volume of whole blood (WB) was obtained from SAM-mice. After the single centrifugation at 150g for 20min, blood was fractionated into two layers: the bottom layer consists of red blood cells (RBC), and the top layer contains platelet rich plasma (PRP). The separated PRP was then centrifuged at 400g for 15min: the bottom consists of platelet pellets (PLT), and the top contains platelet poor plasma (PPP).

  
  
  

• Research Paper pp undefined-undefined

  Amyloid beta biomarker for dementia detection by hyperspectral ophthalmoscope images

  Relevance score: 11.308006

  Yu-Bun Ng, Sheng-Feng Sung, Hong-Thai Nguyen, Shih-Wun Liang, Yu-Ming Tsao, Yi-Hui Kao, Wen-Shou Lin, Hsiang-Chen Wang

  Keywords: dementia detection, hyperspectral imaging, amyloid beta

  Published in Aging on Invalid Date

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  The escalating prevalence and economic burden of dementia underscore the urgency for innovative detection methods. This study investigates the potential of hyperspectral imaging (HSI) to detect dementia by analyzing retinal changes associated with amyloid beta (Aβ) formations. Leveraging a dataset of 3,256 ophthalmoscopic images from 137 participants aged 60 to 85 years, categorized into dementia and non-dementia groups via the Mini-Mental State Examination (MMSE), we extracted features from five key regions of interest (ROIs) identified for their pronounced changes in Aβ biomarkers. The analysis revealed that gender does not significantly influence dementia levels, and no substantial spectral differences were observed within the 380 nm to 600 nm wavelength range. However, significant variations in spectral reflection intensity were noted between 600 nm and 780 nm across both genders, suggesting a potential avenue for distinguishing stages of dementia. Despite the impact of diabetes on the vascular system, its stages did not significantly influence dementia development. This research highlights the utility of HSI in identifying dementia-related retinal changes and calls for further exploration into its effectiveness as a diagnostic tool, potentially offering a non-invasive method for early detection of dementia.

• Research Paper pp undefined-undefined

  Immune-mediated platelet depletion augments Alzheimer’s disease neuropathological hallmarks in APP-PS1 mice

  Relevance score: 10.9161625

  Diana M. Bessa de Sousa, Ariane Benedetti, Barbara Altendorfer, Heike Mrowetz, Michael S. Unger, Katharina Schallmoser, Ludwig Aigner, Kathrin Maria Kniewallner

  Keywords: Alzheimer’s disease, platelets, amyloid-beta, microglia, astrocytes

  Published in Aging on Invalid Date

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  In Alzheimer’s disease (AD), platelets become dysfunctional and might contribute to amyloid beta deposition. Here, we depleted platelets in one-year-old APP Swedish PS1 dE9 (APP-PS1) transgenic mice for five days, using intraperitoneal injections of an anti-CD42b antibody, and assessed changes in cerebral amyloidosis, plaque-associated neuritic dystrophy and gliosis. In APP-PS1 female mice, platelet depletion shifted amyloid plaque size distribution towards bigger plaques and increased neuritic dystrophy in the hippocampus. In platelet-depleted females, plaque-associated Iba1+ microglia had lower amounts of fibrillar amyloid beta cargo and GFAP+ astrocytic processes showed a higher overlap with thioflavin S+ amyloid plaques. In contrast to the popular hypothesis that platelets foster plaque pathology, our data suggest that platelets might limit plaque growth and attenuate plaque-related neuritic dystrophy at advanced stages of amyloid plaque pathology in APP-PS1 female mice. Whether the changes in amyloid plaque pathology are due to a direct effect on amyloid beta deposition or are a consequence of altered glial function needs to be further elucidated.

• Research Paper pp undefined-undefined

  Ginkgolide attenuates memory impairment and neuroinflammation by suppressing the NLRP3/caspase-1 pathway in Alzheimer’s disease

  Relevance score: 9.031441

  Guang-Zhi Liu, Tian-Tong Niu, Qian Yu, Bao-Lei Xu, Xiao-Qing Li, Bo-Yi Yuan, Guo-Bin Yuan, Ting-Ting Yang, Hui-Qin Li, Yi Sun

  Keywords: Alzheimer’s disease, amyloid beta, ginkgolide, microglia, NLRP3 inflammasome

  Published in Aging on Invalid Date

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  The NLRP3 inflammasome is involved in the neuroinflammatory pathway of Alzheimer’s disease (AD). The aim of this study is to explore the roles and underlying mechanisms of ginkgolide (Baiyu®) on amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice and a murine microglial cell line, BV-2. In the present study, the APP/PS1 mice were administered with ginkgolide, followed by a Morris water maze test. The mice were then euthanized to obtain brain tissue for histological and Aβ analysis. Additionally, BV-2 cells pretreated with ginkgolide and then incubated with Aβ1–42 peptide. NLRP3, ASC, and caspase-1 mRNA and protein expression in brain tissue of mice and BV-2 cells were quantified by real-time PCR and Western blotting, as well as reactive oxygen species (ROS) production, interleukin (IL)-1β and IL-18 levels by lucigenin technique and ELISA. Compared with the APP/PS1 mice, ginkgolide-treated mice demonstrated the shortened escape latency, reduced plaques, less inflammatory cell infiltration and neuron loss in the hippocampi of APP/PS1 mice. The levels of NLRP3, ASC, caspase-1, ROS, IL-1β, and IL-18 were also decreased in the brain tissue of APP/PS1 mice or Aβ1–42-treated BV-2 cells following ginkgolide treatment. Ginkgolide exerted protective effects on AD, at least partly by inactivating the NLRP3/caspase-1 pathway.