miR128 up-regulation correlates with impaired amyloid β(1-42) degradation in monocytes from patients with sporadic Alzheimer's disease

Tiribuzi, Roberto; Crispoltoni, Lucia; Porcellati, Serena; Lullo, Martina Di; Florenzano, Fulvio; Pirro, Matteo; Bagaglia, Francesco; Kawarai, Toshitaka; Zampolini, Mauro; Orlacchio, Aldo; Orlacchio, Antonio

doi:10.1016/j.neurobiolaging.2013.08.003

Cited by 136 publications

(96 citation statements)

References 44 publications

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“…Very interestingly, two of these transcripts were micro-RNAs miR128 and miR15a. miR128 is involved in the regulation of amyloid-β degradation in Alzheimer's disease and is involved in tumor suppression (53,54), and miR15a is also involved in tumor growth and its expression is correlated with plaque score in Alzheimer's disease (55,56). A survey of age-related microRNA expression changes in the neuronal stem cell niches of the short-lived annual fish Nothobranchius furzeri found that miR15a was abundant only in older animals (57).…”

Section: Discussionmentioning

confidence: 99%

Effects of aging on circadian patterns of gene expression in the human prefrontal cortex

Chen

Logan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

238

219

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With aging, significant changes in circadian rhythms occur, including a shift in phase toward a “morning” chronotype and a loss of rhythmicity in circulating hormones. However, the effects of aging on molecular rhythms in the human brain have remained elusive. Here, we used a previously described time-of-death analysis to identify transcripts throughout the genome that have a significant circadian rhythm in expression in the human prefrontal cortex [Brodmann’s area 11 (BA11) and BA47]. Expression levels were determined by microarray analysis in 146 individuals. Rhythmicity in expression was found in ∼10% of detected transcripts (P < 0.05). Using a metaanalysis across the two brain areas, we identified a core set of 235 genes (q < 0.05) with significant circadian rhythms of expression. These 235 genes showed 92% concordance in the phase of expression between the two areas. In addition to the canonical core circadian genes, a number of other genes were found to exhibit rhythmic expression in the brain. Notably, we identified more than 1,000 genes (1,186 in BA11; 1,591 in BA47) that exhibited age-dependent rhythmicity or alterations in rhythmicity patterns with aging. Interestingly, a set of transcripts gained rhythmicity in older individuals, which may represent a compensatory mechanism due to a loss of canonical clock function. Thus, we confirm that rhythmic gene expression can be reliably measured in human brain and identified for the first time (to our knowledge) significant changes in molecular rhythms with aging that may contribute to altered cognition, sleep, and mood in later life.

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Section: Discussionmentioning

confidence: 99%

Effects of aging on circadian patterns of gene expression in the human prefrontal cortex

Chen

Logan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

238

219

View full text Add to dashboard Cite

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Section: Alp and Tfeb In Neurodegenerationmentioning

confidence: 99%

“…miR128 is a microRNA identified to be upregulated in the hippocampus of AD patients [76] and in monocytes derived from late-onset AD (LOAD) patients [77]. Of note, miR128 targets TFEB, leading to its downregulation [1,8,77]. In the case of LOAD patient-derived monocytes, lysosomal enzymes and Aβ degradative capacity are reduced compared to healthy donors, likely owing to a decrease in TFEB transcripts and nuclear localization caused by miR128 upregulation [77].…”

Section: Alp and Tfeb In Neurodegenerationmentioning

confidence: 99%

“…Of note, miR128 targets TFEB, leading to its downregulation [1,8,77]. In the case of LOAD patient-derived monocytes, lysosomal enzymes and Aβ degradative capacity are reduced compared to healthy donors, likely owing to a decrease in TFEB transcripts and nuclear localization caused by miR128 upregulation [77]. By contrast, patient-derived fibroblasts containing the familial AD PS1 mutation A246E display lysosomal alkalization and decreased cathepsin D activity, resulting in upregulation of ALP genes, in particular TFEB [78].…”

Section: Alp and Tfeb In Neurodegenerationmentioning

confidence: 99%

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The Autophagy–Lysosomal Pathway in Neurodegeneration: A TFEB Perspective

Martini‐Stoica

Ballabio

et al. 2016

Trends in Neurosciences

358

270

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The autophagy–lysosomal pathway (ALP) is involved in the degradation of long-lived proteins. Deficits in the ALP result in protein aggregation, the generation of toxic protein species, and accumulation of dysfunctional organelles, which are hallmarks of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and prion disease. Decades of research have therefore focused on enhancing the ALP in neurodegenerative diseases. More recently, transcription factor EB (TFEB), a major regulator of autophagy and lysosomal biogenesis, has emerged as a leading factor in addressing disease pathology. We review the regulation of the ALP and TFEB and their impact on neurodegenerative diseases. We also offer our perspective on the complex role of autophagy and TFEB in disease pathogenesis and its therapeutic implications through the examination of prion disease.

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“…Not withstanding, recent studies reported conflicting results. In these studies CatB was found less expressed in patients with dementia and CatB deletion by its inhibitors increased Aß levels (Wang et al, 2012; Tiribuzi et al, 2014). In such works, overexpression of CatB lowered Aß levels (Mueller-Steiner et al, 2006; Yang et al, 2011; Wang et al, 2012).…”

Section: Introductionmentioning

confidence: 89%

Cathepsin B Improves ß-Amyloidosis and Learning and Memory in Models of Alzheimer’s Disease

Embury

Dyavarshetty

et al. 2016

J Neuroimmune Pharmacol

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Amyloid-ß (Aß) precursor protein (APP) metabolism engages neuronal endolysosomal pathways for Aß processing and secretion. In Alzheimer’s disease (AD), dysregulation of APP leads to excess Aß and neuronal dysfunction; suggesting that neuronal APP/Aß trafficking can be targeted for therapeutic gain. Cathepsin B (CatB) is a lysosomal cysteine protease that can lower Aß levels. However, whether CatB-modulation of Aß improves learning and memory function deficits in AD is not known. To this end, progenitor neurons were infected with recombinant adenovirus expressing CatB and recovered cell lysates subjected to proteomic analyses. The results demonstrated Lamp1 deregulation and linkages between CatB and the neuronal phagosome network. Hippocampal injections of adeno-associated virus expressing CatB reduced Aß levels, increased Lamp1 and improved learning and memory. The findings were associated with the emergence of c-fos + cells. The results support the idea that CatB can speed Aß metabolism through lysosomal pathways and as such reduce AD-associated memory deficits.Electronic supplementary materialThe online version of this article (doi:10.1007/s11481-016-9721-6) contains supplementary material, which is available to authorized users.

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miR128 up-regulation correlates with impaired amyloid β(1-42) degradation in monocytes from patients with sporadic Alzheimer's disease

Cited by 136 publications

References 44 publications

Effects of aging on circadian patterns of gene expression in the human prefrontal cortex

Effects of aging on circadian patterns of gene expression in the human prefrontal cortex

The Autophagy–Lysosomal Pathway in Neurodegeneration: A TFEB Perspective

Cathepsin B Improves ß-Amyloidosis and Learning and Memory in Models of Alzheimer’s Disease

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