Abstract Accumulation of amyloid β (Aβ) in the brain is a key pathological hallmark of Alzheimer's disease ( AD ). Because aging is the most prominent risk factor for AD , understanding the molecular changes during aging is likely to provide critical insights into AD pathogenesis. However, studies on the role of mi RNA s in aging and AD pathogenesis have only recently been initiated. Identifying mi RNA s dysregulated by the aging process in the brain may lead to novel understanding of molecular mechanisms of AD pathogenesis. Here, we identified that miR‐186 levels are gradually decreased in cortices of mouse brains during aging. In addition, we demonstrated that miR‐186 suppresses β‐site amyloid precursor protein‐cleaving enzyme 1 ( BACE 1) expression by directly targeting the 3′ UTR of Bace1 mRNA in neuronal cells. In contrast, inhibition of endogenous miR‐186 significantly increased BACE 1 levels in neuronal cells. Importantly, miR‐186 over‐expression significantly decreased Aβ level by suppressing BACE 1 expression in cells expressing human pathogenic mutant amyloid precursor protein. Taken together, our data demonstrate that miR‐186 is a potent negative regulator of BACE 1 in neuronal cells and it may be one of the molecular links between brain aging and the increased risk for AD during aging. image We identified that miR‐186 levels are gradually decreased in mouse cortices during aging. Furthermore, we demonstrated that miR‐186 is a novel negative regulator of beta‐site amyloid precursor protein‐cleaving enzyme 1 (BACE1) expression in neuronal cells. Therefore, we proposed that reduction in miR‐186 levels during aging may lead to the up‐regulation of BACE1 in the brain, thereby increasing a risk for Alzheimer's disease in aged individuals. Read the Editorial Highlight for this article on page 308 .
Apolipoprotein E (ApoE) is the strongest genetic risk factor for Alzheimer's disease and has been implicated in the risk for other neurological disorders.The three common ApoE isoforms (ApoE2, E3, and E4) each differ by a single amino acid, with ApoE4 increasing and ApoE2 decreasing the risk of Alzheimer's disease (AD).Both the isoform and amount of ApoE in the brain modulate AD pathology by altering the extent of amyloid beta (Ab) peptide deposition.Therefore, quantifying ApoE isoform production and clearance rates may advance our understanding of the role of ApoE in health and disease.To measure the kinetics of ApoE in the central nervous system (CNS), we applied in vivo stable isotope labeling to quantify the fractional turnover rates of ApoE isoforms in 18 cognitively-normal adults and in ApoE3 and ApoE4 targeted-replacement mice.No isoform-specific differences in CNS ApoE3 and ApoE4 turnover rates were observed when measured in human CSF or mouse brain.However, CNS and peripheral ApoE isoform turnover rates differed substantially, which is consistent with previous reports and suggests that the pathways responsible for ApoE metabolism are different in the CNS and the periphery.We also demonstrate a slower turnover rate for CSF ApoE than that for amyloid beta, another molecule critically important in AD pathogenesis.
Abstract Abnormal protein accumulation and mislocalization is a general hallmark of Alzheimer disease. Recent data suggest nucleocytoplasmic transport may be compromised by tau in Alzheimer disease. In this context, we have examined the RNA polymerase II subunit RPB1, which is the catalytic subunit that plays a critical role in transcription. Using immunofluorescence staining in control and Alzheimer disease hippocampal tissue, we show that 2 phosphoisoforms of RPB1 mislocalize from the nucleus to the cytoplasm of neurons in Alzheimer disease. The number of neurons with this cytoplasmic mislocalization is correlated with the burden of pathologic tau (AT8-immunopositive neurons). In order to test whether there is a causal relationship between pathologic tau and cytoplasmic RPB1 accumulation, we used the rTg4510 mouse model, which expresses a regulatable pathologic human tau species harboring the P301L mutation. Using immunofluorescence staining on brain tissue from young (2.5-month-old) and aged (8.5- to 10-month-old) rTg4510 mice, we found a tau- and age-dependent increase in cytoplasmic mislocalization of Rpb1. In summary, this study provides evidence that tau induces mislocalization of RPB1 in Alzheimer disease, and since RPB1 is essential for transcription, this raises the possibility that RPB1 mislocalization could lead to fundamental alterations in neuronal health.
Autophagy is a tightly regulated lysosomal degradation/recycling pathway, critical for cellular homeostasis, such as neuronal survival and death. Impaired autophagic function has been reported in several neurodegenerative diseases, such as Parkinson’s, Huntington’s and Alzheimer’s disease (AD). AD is the most common cause of dementia in the elderly and it is characterized by progressive memory loss and cognitive decline along with synaptic dysfunction. Accumulations of amyloid β (Aβ) and tau proteins are two major neuropathological hallmarks of AD. In addition, accumulation of autophagic vacuoles and other autophagic pathology are evident in dystrophic neurites of AD brains. A series of studies has suggested that autophagy is involved in metabolism of Aβ and tau. Moreover, presenilin (PS), a core subunit of γ- secretase complex, has been demonstrated to play an important role in autophagy at the level of lysosomal proteolysis. In spite of several therapeutic approaches through modulation of autophagic pathway, inconsistent results among studies have made it difficult to determine whether autophagy induction will be beneficial or detrimental for AD pathogenesis. Therefore, roles of autophagy in AD need to be further investigated to develop therapeutic strategies in the future. Keywords: Autophagy, mTOR, rapamycin, beclin, Alzheimer’s disease.
APOE4 genotype is the strongest genetic risk factor for Alzheimer's disease. Prevailing evidence suggests that amyloid β plays a critical role in Alzheimer's disease. The objective of this article is to review the recent findings about the metabolism of apolipoprotein E (ApoE) and amyloid β and other possible mechanisms by which ApoE contributes to the pathogenesis of Alzheimer's disease.ApoE isoforms have differential effects on amyloid β metabolism. Recent studies demonstrated that ApoE-interacting proteins, such as ATP-binding cassette A1 (ABCA1) and LDL receptor, may be promising therapeutic targets for Alzheimer's disease treatment. Activation of liver X receptor and retinoid X receptor pathway induces ABCA1 and other genes, leading to amyloid β clearance. Inhibition of the negative regulators of ABCA1, such as microRNA-33, also induces ABCA1 and decreases the levels of ApoE and amyloid β. In addition, genetic inactivation of an E3 ubiquitin ligase, myosin regulatory light chain interacting protein, increases LDL receptor levels and inhibits amyloid accumulation. Although amyloid β-dependent pathways have been extensively investigated, there have been several recent studies linking ApoE with vascular function, neuroinflammation, metabolism, synaptic plasticity, and transcriptional regulation. For example, ApoE was identified as a ligand for a microglial receptor, TREM2, and studies suggested that ApoE may affect the TREM2-mediated microglial phagocytosis.Emerging data suggest that ApoE affects several amyloid β-independent pathways. These underexplored pathways may provide new insights into Alzheimer's disease pathogenesis. However, it will be important to determine to what extent each mechanism contributes to the pathogenesis of Alzheimer's disease.
Bone is a dynamic mineralized tissue that undergoes continuous turnover throughout life. While the general mechanism of bone mineral metabolism is documented, the role of underlying collagen structures in regulating osteoblastic mineral deposition and osteoclastic mineral resorption remains an active research area, partly due to the lack of biomaterial platforms supporting accurate and analytical investigation. The recently introduced osteoid-inspired demineralized bone paper (DBP), prepared by 20-μm thin sectioning of demineralized bovine compact bone, holds promise in addressing this challenge as it preserves the intrinsic bony collagen structure and retains semi-transparency. Here, we report on the impact of collagen structures on modulating osteoblast and osteoclast-driven bone mineral metabolism using vertical and transversal DBPs that exhibit a uniaxially aligned and a concentric ring collagen structure, respectively. Translucent DBP reveals these collagen structures and facilitates longitudinal tracking of mineral deposition and resorption under brightfield microscopy for at least 3 wk. Genetically labeled primary osteogenic cells allow fluorescent monitoring of these cellular processes. Osteoblasts adhere and proliferate following the underlying collagen structures of DBPs. Osteoblastic mineral deposition is significantly higher in vertical DBP than in transversal DBP. Spatiotemporal analysis reveals notably more osteoblast adhesion and faster mineral deposition in vascular regions than in bone regions. Subsequent osteoclastic resorption follows these mineralized collagen structures, directing distinct trench and pit-type resorption patterns. In vertical DBP, trench-type resorption occurs at an 80% frequency, whereas transversal DBP shows 35% trench-type and 65% pit-type resorption. Our studies substantiate the importance of collagen structures in regulating mineral metabolism by osteogenic cells. DBP is expected to serve as an enabling biomaterial platform for studying various aspects of cellular and extracellular bone remodeling biology.
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