Alzheimer's disease (AD) is the most common form of dementia and is marked with cognitive impairment, cell loss, and reduction of life expectancy. Pathologically, senile plaque, beta-amyloid (Aβ) aggregates, and neurofibrillary tangle, tau aggregates, are the hallmark of the disease. Although genetics studies provide a causative link between the disease and Aβ accumulation, the interaction between Aβ and tau and its contribution to the
Accumulated Aβ is one of the hallmarks of Alzheimer's disease. Although accumulated results from in vivo and in vitro studies have shown that accumulated Aβ causes learning and memory deficit, cell death, and lifespan reduction, the underlying mechanism remains elusive. In neurons, calcium dynamics is regulated by voltage‐gated calcium channel (VGCC) and endoplasmic reticulum and is important for neuron survival and formation of learning and memory. The current study employs in vivo genetics to reveal the role of calcium regulation systems in Aβ‐induced behavioral damage. Our data shows that although increased VGCC improves learning and memory in Aβ42 flies, reduction of VGCC and Inositol trisphosphate receptors extends Aβ42 flies' lifespan and improves cell viability. The complex role of calcium regulation systems in Aβ‐induced damage suggests that the imbalance of calcium dynamic is one of the main factors to trigger learning and memory deficit and cell death in the disease.
Amyloid cascade hypothesis proposes that amyloid β (Aβ) accumulation is the initiator and major contributor to the development of Alzheimer’s disease (AD). However, this hypothesis has recently been challenged by clinical studies showing that reduction of Aβ accumulation in the brain does not accompany with cognitive improvement, suggesting that therapeutically targeting Aβ in the brain may not be sufficient for restoring cognitive function. Since the molecular mechanism underlying the progressive development of cognitive impairment after Aβ clearance is largely unknown, the reason of why there is no behavioral improvement after Aβ clearance remains elusive. In the current study, we demonstrated that transient Aβ expression caused learning deficit in later life, despite the accumulated Aβ was soon being removed after the expression. Early Aβ exposure decreased the cellular expression of XBP1 and both the antioxidants, catalase, and dPrx5, which made cells more vulnerable to oxidative stress in later life. Early induction of XBP1, catalase, and dPrx5 prevented the overproduction of ROS, improved the learning performance, and preserved the viability of cells in the later life with the early Aβ induction. Treating the early Aβ exposed flies with antioxidants such as vitamin E, melatonin and lipoic acid, after the removal of Aβ also preserved the learning ability in later life. Taken together, we demonstrated that early and transient Aβ exposure can have a profound impact on animal behavior in later life and also revealed the cellular and molecular mechanism underlying the development of learning impairment by the early and transient Aβ exposure.
Background:A significant proportion of amyloid-beta (Ab) peptides in Alzheimer's disease (AD) is truncated at the N-terminus. Among these, accumulation of pGlu-modified amyloid (pGlu-Ab3-40/42) has been shown to correlate with disease progression and tau pathology. Therapeutic strategies targeting pGlu-Ab, e.g. inhibitors of glutaminyl cyclase (QC) that catalyzes pGlu-formation, are currently in clinical assessment. However, it is still unclear, which enzyme(s) might be responsible for N-truncation of Ab and thus, generation of QC substrates. Aim of the study was to characterize the potential formation of the precursor(s) of pGlu-Ab3-40/42 by Meprin b in cell culture. Methods:We expressed different APP proteins (wt or familial Alzheimer's mutations) in the cell lines HEK293 and CHO. The APP processing and production was assessed using Western Blot analysis and ELISAs detecting N-truncated or full length Ab. Maldi-TOF mass spectrometry was used to analyze cleavage of APP-derived peptides. Results: An in vitro analysis of cleavage of APP-related peptides suggested specificity of Meprin b for the b-site of APP. The primary cleavage products were Ab(1-x), Ab(2-x) and, to a lesser extent, Ab(3-x). In cell culture, co-expression of APP and Meprin b, but not of its isoenzyme Meprin a, resulted in production of N-truncated Ab peptides, primarily Ab(2-40/42). Thereby, Meprin b cleaved preferably APPwt and not APPswedish, which contrasts to the b-secretase BACE. The cleavage of APP resulted also in minor amounts of Ab(3-40/42), which was revealed by addition of human QC and application of highly sensitive ELISA detecting pGlu-Ab3-40/42. Finally, analysis of human brain samples revealed upregulation of Meprin b, but not Meprin a, in AD. Meprin b positive astrocytes are found in the vicinity of pGlu-Ab containing deposits in human tissue. Conclusions: The data support a BACE-independent processing of APPwt that may contribute to formation of N-truncated Ab. These truncated forms, in turn, might be prone to further post-translational modification. Thus, Meprin b might represent a potential upstream target to suppress formation of pGlu-Ab.
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