Aß-Induced Alterations in Membrane Lipids Occur before Synaptic Loss Appears.

Loss of active synapses and alterations in membrane lipids are crucial events in physiological aging as well as in neurodegenerative disorders. Both are related to the abnormal aggregation of amyloid-beta (Aß) species, generally known as amyloidosis. There are two major known human Aß species: Aß(1-40) and Aß(1-42). However, which of these species have more influence on active synapses and membrane lipids is still poorly understood. Additionally, the time-dependent effect of Aß species on alterations in membrane lipids of hippocampal neurones and glial cells remains unknown. Therefore, our study contributes to a better understanding of the role of Aß species in the loss of active synapses and the dysregulation of membrane lipids in vitro. We showed that Aß(1-40) or Aß(1-42) treatment influences membrane lipids before synaptic loss appears and that the loss of active synapses is not dependent on the Aß species. Our lipidomic data analysis showed early changes in specific lipid classes such as sphingolipid and glycerophospholipid neurones. Our results underscore the potential role of lipids as a possible early diagnostic biomarker in amyloidosis-related disorders.

Are N- and C-terminally truncated Aß species key pathological triggers in Alzheimer's disease?

The histopathology of Alzheimer's disease (AD) is characterized by neuronal loss, neurofibrillary tangles, and senile plaque formation. The latter results from an exacerbated production (familial AD cases) or altered degradation (sporadic cases) of 40/42-amino acid-long ß-amyloid peptides (Aß peptides) that are produced by sequential cleavages of Aß precursor protein (ßAPP) by ß- and γ-secretases. The amyloid cascade hypothesis proposes a key role for the full-length Aß42 and the Aß40/42 ratio in AD etiology, in which soluble Aß oligomers lead to neurotoxicity, tau hyperphosphorylation, aggregation, and, ultimately, cognitive defects. However, following this postulate, during the last decade, several clinical approaches aimed at decreasing full-length Aß42 production or neutralizing it by immunotherapy have failed to reduce or even stabilize AD-related decline. Thus, the Aß peptide (Aß40/42)-centric hypothesis is probably a simplified view of a much more complex situation involving a multiplicity of APP fragments and Aß catabolites. Indeed, biochemical analyses of AD brain deposits and fluids have unraveled an Aß peptidome consisting of additional Aß-related species. Such Aß catabolites could be due to either primary enzymatic cleavages of ßAPP or secondary processing of Aß itself by exopeptidases. Here, we review the diversity of N- and C-terminally truncated Aß peptides and their biosynthesis and outline their potential function/toxicity. We also highlight their potential as new pharmaceutical targets and biomarkers.

A Near-infrared Fluorescence and Positron Emission Tomography Bimodal Probe for In Vivo Imaging of Amyloid-ß Species.

Noninvasive imaging of amyloid-ß (Aß) species in vivo is important for the early diagnosis of Alzheimer's disease (AD). In this paper, we report a near-infrared (NIR) fluorescence (FL) and positron emission tomography (PET) bimodal probe (NIR-[68Ga]) for in vivo imaging of both soluble and insoluble Aß species. NIR-[68Ga] holds a high binding affinity, high selectivity and high sensitivity toward Aß42 monomers, oligomers, and aggregates in vitro. In vivo imaging results show that NIR-[68Ga] can cross the blood-brain-barrier (BBB), and produce significantly higher PET and NIR FL bimodal signals in the brains of APP/PS1 transgenic AD mice relative to that of age-matched wild-type mice, which are also validated by the ex vivo autoradiography and histological staining images. Our results demonstrate that NIR-[68Ga] is an efficient NIR FL and PET bimodal probe for the sensitive imaging of soluble and insoluble Aß species in AD mice.

Recent Advances in the Development of Near-Infrared Fluorescent Probes for the in Vivo Brain Imaging of Amyloid-ß Species in Alzheimer's Disease.

The deposition of ß-amyloid (Aß) plaques in the parenchymal and cortical regions of the brain of Alzheimer's disease (AD) patients is considered the foremost pathological hallmark of the disease. The early diagnosis of AD is paramount in order to effective management and treatment of the disease. Developing near-infrared fluorescence (NIRF) probes targeting Aß species is a potential and attractive approach suitable for the early and timely diagnosis of AD. The advantages of the NIRF probes over other tools include real-time detection, higher sensitivity, resolution, comparatively inexpensive experimental setup, and noninvasive nature. Currently, enormous progress is being observed in the development of NIRF probes for the in vivo imaging of Aß species. Several strategies, i.e., the classical push-pull approach, "turn-on" effect, aggregation-induced emission (AIE), and resonance energy transfer (RET), have been exploited for development. We have outlined and discussed the recently emerged NIRF probes with different design strategies targeting Aß species for ex vivo and in vivo imaging. We believe that understanding the recent development enables the prospect of the rational design of probes and will pave the way for developing future novel probes for early diagnosis of AD.

Understanding the Binding Mechanism of Amyloid-ß Inhibitors from Molecular Simulations.

In recent years, Aß aggregation prevention, one of the most concerned strategies in drug development has been carefully assessed to treat Alzheimer's disease. Aß peptides can transform structurally from random coil monomer into ß-stranded protofibril via multiple oligomeric states. Among the various Aß species, the identification of binding targets has been challenging due to the heterogeneity and metastable nature. A better understanding of Aß species' assembly details and structural properties has been more characterized recently. Numerous potential inhibitors have been identified that they can effectively bind to different Aß species such as monomer, oligomer or protofibril during the inhibition of Aß aggregation process. This review highlights the diversity of structural ensembles of Aß species, from monomer to protofibril forms and the specific binding targets by their potential inhibitors. Comprehending the binding mechanism of Aß inhibitors is indispensable for searching novel drug candidates against early-stage Alzheimer's disease.

Neurotoxic Effects of Aß6-42 Peptides Mimicking Putative Products Formed by the Angiotensin Converting Enzyme.

Angiotensin converting enzyme (ACE) is involved in proteolytic processing of the amyloid-ß(Aß) peptide implicated in the development of Alzheimer's disease (AD) and known products of ACE-based processing of Aß42 are characterized by reduced aggregability and cytotoxicity. Recently it has been demonstrated that ACE can act as an arginine specific endopeptidase cleaving the N-terminal pentapeptide (Aß1-5) from synthetic Aß peptide analogues. In the context of proteolytic processing of full length Aß42, this suggests possible formation of Aß6-42 species. The aim of this study was to test a hypothesis that some N-terminally truncated Aß peptide(s) could retain aggregability and neurotoxic properties typical for Aß42. We have investigated aggregability of two amyloid-ß peptides, Aß6-42 and isoD7-Aß6-42, mimicking potential proteolytic products of Aß42 and isoD7-Aß42, and evaluated their effects on the repertoire of brain Aß binding proteins, and cytotoxicity towards neuroblastoma SH-SY5Y cells. Aggregability of isoD7-Aß6-42 and Aß6-42 was higher than that of full-length peptides Aß42 and isoD7-Aß42, while the repertoire of mouse brain Aß binding proteins dramatically decreased. Aß6-42 and isoD7-Aß6-42 exhibited higher neurotoxicity towards SH-SY5Y cells than Aß42 and isoD7-Aß42, respectively. They effectively stimulated production of ROS and NO, and also TNFα secretion by cells. Thus, our results suggest that ACE-dependent processing of full-length Aßs could result in formation of more pathogenic peptides.