Dataset Information

Reduced amyloid deposition in mice overexpressing RTN3 is adversely affected by preformed dystrophic neurites.

ABSTRACT: Reticulon 3 (RTN3) was initially identified as a negative modulator of BACE1, an enzyme that cleaves amyloid precursor protein (APP) to release beta-amyloid peptide. Interestingly, RTN3 can also form aggregates after accumulation, and increased RTN3 aggregation correlates with the formation of RTN3 immunoreactive dystrophic neurites (RIDNs) in brains of Alzheimer's cases. Transgenic mice expressing RTN3 alone develop RIDNs in their hippocampus but not in their cortex. To determine the in vivo effects of RTN3 and preformed RIDNs on amyloid deposition, we crossed bitransgenic mice expressing APP and presenilin 1 (PS1) mutations with mice overexpressing RTN3. We found that amyloid deposition in cortex, the hippocampal CA3 region, and dentate gyrus was significantly reduced in triple transgenic mice compared with bitransgenic controls. However, reduction of amyloid deposition in the hippocampal CA1 region, where RIDNs predominantly formed before amyloid deposition, was less significant. Hence, preformed RTN3 aggregates in RIDNs clearly offset the negative modulation of BACE1 activity by RTN3. Furthermore, our study indicates that the increased expression of RTN3 could result in an alteration of BACE1 intracellular trafficking by retaining more BACE1 in the endoplasmic reticulum compartment where cleavage of APP by BACE1 is less favored. Our results suggest that inhibition of RTN3 aggregation is likely to be beneficial by reducing both amyloid deposition and the formation RIDNs.

SUBMITTER: Shi Q

PROVIDER: S-EPMC2743151 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Reduced amyloid deposition in mice overexpressing RTN3 is adversely affected by preformed dystrophic neurites.

Shi Qi Q Prior Marguerite M He Wanxia W Tang Xiangying X Hu Xiangyou X Yan Riqiang R

The Journal of neuroscience : the official journal of the Society for Neuroscience 20090701 29

Reticulon 3 (RTN3) was initially identified as a negative modulator of BACE1, an enzyme that cleaves amyloid precursor protein (APP) to release beta-amyloid peptide. Interestingly, RTN3 can also form aggregates after accumulation, and increased RTN3 aggregation correlates with the formation of RTN3 immunoreactive dystrophic neurites (RIDNs) in brains of Alzheimer's cases. Transgenic mice expressing RTN3 alone develop RIDNs in their hippocampus but not in their cortex. To determine the in vivo ef ...[more]

PMID: 19625507

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Project description:Alzheimer's disease (AD) is characterized by amyloid plaques composed of the β-amyloid (Aβ) peptide surrounded by swollen presynaptic dystrophic neurites consisting of dysfunctional axons and terminals that accumulate the β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) required for Aβ generation. The cellular and molecular mechanisms that govern presynaptic dystrophic neurite formation are unclear, and elucidating these processes may lead to novel AD therapeutic strategies. Previous studies suggest Aβ may disrupt microtubules, which we hypothesize have a critical role in the development of presynaptic dystrophies. To investigate this further, here we have assessed the effects of Aβ, particularly neurotoxic Aβ42, on microtubules during the formation of presynaptic dystrophic neurites in vitro and in vivo. Live-cell imaging of primary neurons revealed that exposure to Aβ42 oligomers caused varicose and beaded neurites with extensive microtubule disruption, and inhibited anterograde and retrograde trafficking. In brain sections from AD patients and the 5XFAD transgenic mouse model of amyloid pathology, dystrophic neurite halos with BACE1 elevation around amyloid plaques exhibited aberrant tubulin accumulations or voids. At the ultrastructural level, peri-plaque dystrophies were strikingly devoid of microtubules and replete with multi-lamellar vesicles resembling autophagic intermediates. Proteins of the microtubule motors, kinesin and dynein, and other neuronal proteins were aberrantly localized in peri-plaque dystrophies. Inactive pro-cathepsin D also accumulated in peri-plaque dystrophies, indicating reduced lysosomal function. Most importantly, BACE1 accumulation in peri-plaque dystrophies caused increased BACE1 cleavage of APP and Aβ generation. Our study supports the hypothesis that Aβ induces microtubule disruption in presynaptic dystrophic neurites that surround plaques, thus impairing axonal transport and leading to accumulation of BACE1 and exacerbation of amyloid pathology in AD.

Project description:Modern agriculture, in seeking to maximize yields to meet growing global food demand, has caused loss of soil organic carbon (SOC) and compaction, impairing critical regulating and supporting ecosystem services upon which humans also depend. Own-growing makes an important contribution to food security in urban areas globally, but its effects on soil qualities that underpin ecosystem service provision are currently unknown. We compared the main indicators of soil quality; SOC storage, total nitrogen (TN), C : N ratio and bulk density (BD) in urban allotments to soils from the surrounding agricultural region, and between the allotments and other urban greenspaces in a typical UK city. A questionnaire was used to investigate allotment management practices that influence soil properties. Allotment soils had 32% higher SOC concentrations and 36% higher C : N ratios than pastures and arable fields and 25% higher TN and 10% lower BD than arable soils. There was no significant difference between SOC concentration in allotments and urban non-domestic greenspaces, but it was higher in domestic gardens beneath woody vegetation. Allotment soil C : N ratio exceeded that in non-domestic greenspaces, but was lower than that in garden soil. Three-quarters of surveyed allotment plot holders added manure, 95% composted biomass on-site, and many added organic-based fertilizers and commercial composts. This may explain the maintenance of SOC, C : N ratios, TN and low BD, which are positively associated with soil functioning. Synthesis and applications. Maintenance and protection of the quality of our soil resource is essential for sustainable food production and for regulating and supporting ecosystem services upon which we depend. Our study establishes, for the first time, that small-scale urban food production can occur without the penalty of soil degradation seen in conventional agriculture, and maintains the high soil quality seen in urban greenspaces. Given the involvement of over 800 million people in urban agriculture globally, and its important contribution to food security, our findings suggest that to better protect soil functions, local, national and international urban planning and policy making should promote more urban own-growing in preference to further intensification of conventional agriculture to meet increasing food demand.

Dataset Information

Reduced amyloid deposition in mice overexpressing RTN3 is adversely affected by preformed dystrophic neurites.

Publications

Reduced amyloid deposition in mice overexpressing RTN3 is adversely affected by preformed dystrophic neurites.

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