Citations

AbstractAccumulation 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 miRNAs in aging and AD pathogenesis have only recently been initiated. Identifying miRNAs 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 (BACE1) expression by directly targeting the 3′UTR of Bace1 mRNA in neuronal cells. In contrast, inhibition of endogenous miR‐186 significantly increased BACE1 levels in neuronal cells. Importantly, miR‐186 over‐expression significantly decreased Aβ level by suppressing BACE1 expression in cells expressing human pathogenic mutant amyloid precursor protein. Taken together, our data demonstrate that miR‐186 is a potent negative regulator of BACE1 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.

Inhibiting the E3 ubiquitin ligase Idol in a mouse model of Alzheimer’s-like pathology ameliorates disease severity by promoting clearance of Aβ peptides by microglia.

A number of hypotheses regarding how anti‐Aβ antibodies alter amyloid deposition have been postulated, yet there is no consensus as to how Aβ immunotherapy works. We have examined the in vivo binding properties, pharmacokinetics, brain penetrance, and alterations in Aβ levels after a single peripheral dose of anti‐Aβ antibodies to both wild‐type (WT) and young non‐Aβ depositing APP and BRI‐Aβ42 mice. The rapid rise in plasma Aβ observed after antibody (Ab) administration is attributable to prolongation of the half‐life of Aβ bound to the Ab. Only a miniscule fraction of Ab enters the brain, and despite dramatic increases in plasma Aβ, we find no evidence that total brain Aβ levels are significantly altered. Surprisingly, cerebral spinal fluid Aβ levels transiently rise, and when Ab:Aβ complex is directly injected into the lateral ventricles of mice, it is rapidly cleared from the brain into the plasma where it remains stable. When viewed in context of daily turnover of Aβ, these data provide a framework to evaluate proposed mechanisms of Aβ attenuation mediated by peripheral administration of an anti‐Aβ monoclonal antibody (mAb) effective in passive immunization paradigm. Such quantitative data suggest that the mAbs are either indirectly enhancing clearance of Aβ or targeting a low abundance aggregation intermediate.—Levites, Y., Smithson, L. A., Price, R. W., Dakin. R. S., Yuan, B., Sierks, M. R., Kim, J., McGowan, E., Reed, D. K., Rosenberry, T. L., Das, P., Golde, T. E. Insights into the mechanisms of action of anti‐Aβ antibodies in Alzheimer's disease mouse models. FASEB J. 20, E2002–E2014 (2006)