Amyloid-Independent Mechanisms in Alzheimer's Disease Pathogenesis

Despite the progress of the past two decades, the cause of Alzheimer's disease (AD) and effective treatments against it remain elusive. The hypothesis that amyloid-β (Aβ) peptides are the primary causative agents of AD retains significant support among researchers. Nonetheless, a growing body of evidence shows that Aβ peptides are unlikely to be the sole factor in AD etiology. Evidence that Aβ/amyloid-independent factors, including the actions of AD-related genes, also contribute significantly to AD pathogenesis was presented in a symposium at the 2010 Annual Meeting of the Society for Neuroscience. Here we summarize the studies showing how amyloid-independent mechanisms cause defective endo-lysosomal trafficking, altered intracellular signaling cascades, or impaired neurotransmitter release and contribute to synaptic dysfunction and/or neurodegeneration, leading to dementia in AD. A view of AD pathogenesis that encompasses both the amyloid-dependent and -independent mechanisms will help fill the gaps in our knowledge and reconcile the findings that cannot be explained solely by the amyloid hypothesis.National Institutes of Health (U.S.) (Grant P01-AG027916)National Institutes of Health (U.S.) (Grant R01-NS051874

Endocannabinoid System: Emerging Role from Neurodevelopment to Neurodegeneration

Abstract: The endocannabinoid system, including endogenous ligands ('endocannabinoids' ECs), their receptors, synthesizing and degrading enzymes, as well as transporter molecules, has been detected from the earliest stages of embryonic development and throughout pre-and postnatal development. ECs are bioactive lipids, which comprise amides, esters and ethers of long chain polyunsaturated fatty acids. Anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol (2-AG) are the best studied ECs, and act as agonists of cannabinoid receptors. Thus, AEA and 2-AG mimic several pharmacological effects of the exogenous cannabinoid delta9-tetrahydrocannabinol ( 9 -THC), the psychoactive principle of cannabis sativa preparations like hashish and marijuana. Recently, however, several lines of evidence have suggested that the EC system may play an important role in early neuronal development as well as a widespread role in neurodegeneration disorders. Many of the effects of cannabinoids and ECs are mediated by two G proteincoupled receptors (GPCRs), CB1 and CB2, although additional receptors may be implicated. Both CB1 and CB2 couple primarily to inhibitory G proteins and are subject to the same pharmacological influences as other GPCRs. This new system is briefly presented in this review, in order to put in a better perspective the role of the EC pathway from neurodevelopment to neurodegenerative disorders, like Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. In addition, the potential exploitation of antagonists of CB1 receptors, or of inhibitors of EC metabolism, as next-generation therapeutics is discussed

The neurofilament middle molecular mass subunit carboxyl-terminal tail domains is essential for the radial growth and cytoskeletal architecture of axons but not for regulating neurofilament transport rate

The phosphorylated carboxyl-terminal “tail” domains of the neurofilament (NF) subunits, NF heavy (NF-H) and NF medium (NF-M) subunits, have been proposed to regulate axon radial growth, neurofilament spacing, and neurofilament transport rate, but direct in vivo evidence is lacking. Because deletion of the tail domain of NF-H did not alter these axonal properties (Rao, M.V., M.L. Garcia, Y. Miyazaki, T. Gotow, A. Yuan, S. Mattina, C.M. Ward, N.S. Calcutt, Y. Uchiyama, R.A. Nixon, and D.W. Cleveland. 2002. J. Cell Biol. 158:681–693), we investigated possible functions of the NF-M tail domain by constructing NF-M tail–deleted (NF-MtailΔ) mutant mice using an embryonic stem cell–mediated “gene knockin” approach that preserves normal ratios of the three neurofilament subunits. Mutant NF-MtailΔ mice exhibited severely inhibited radial growth of both motor and sensory axons. Caliber reduction was accompanied by reduced spacing between neurofilaments and loss of long cross-bridges with no change in neurofilament protein content. These observations define distinctive functions of the NF-M tail in regulating axon caliber by modulating the organization of the neurofilament network within axons. Surprisingly, the average rate of axonal transport of neurofilaments was unaltered despite these substantial effects on axon morphology. These results demonstrate that NF-M tail–mediated interactions of neurofilaments, independent of NF transport rate, are critical determinants of the size and cytoskeletal architecture of axons, and are mediated, in part, by the highly phosphorylated tail domain of NF-M

Modeling approach to regime shifts of primary production in shallow coastal ecosystems

Pristine coastal shallow systems are usually dominated by extensive meadows of seagrass species, which are assumed to take advantage of nutrient supply from sediment. An increasing nutrient input is thought to favour phytoplankton, epiphytic microalgae, as well as opportunistic ephemeral macroalgae that coexist with seagrasses. The primary cause of shifts and succession in the macrophyte community is the increase of nutrient load to water; however temperature plays also an important role. A competition model between rooted seagrass (Zostera marina), macroalgae (Ulva sp), and phytoplankton has been developed to analyse the succession of primary producer communities in these systems. Successions of dominance states, with different resilience characteristics, are found when modifying the input of nutrients and the seasonal temperature and light intensity forcing.Comment: 33 pages, including 10 figures. To appear in Ecological Complexit

Automated pastures and the digital divide: how agricultural technologies are shaping labour and rural communities

A “digital revolution” in agriculture is underway. Advanced technologies like sensors, artificial intelligence, and robotics are increasingly being promoted as a means to increase food production efficiency while minimizing resource use. In the process, agricultural digitalization raises critical social questions about the implications for diverse agricultural labourers and rural spaces as digitalization evolves. In this paper, we use literature and field data to outline some key trends being observed at the nexus of agricultural production, technology, and labour in North America, with a particular focus on the Canadian context. Using the data, we highlight three key tensions observed: rising land costs and automation; the development of a high-skill/low-skilled bifurcated labour market; and issues around the control of digital data. With these tensions in mind, we use a social justice lens to consider the potential implications of digital agricultural technologies for farm labour and rural communities, which directs our attention to racial exploitation in agricultural labour specifically. In exploring these tensions, we argue that policy and research must further examine how to shift the trajectory of digitalization in ways that support food production as well as marginalized agricultural labourers, while pointing to key areas for future research—which is lacking to date. We emphasize that the current enthusiasm for digital agriculture should not blind us to the specific ways that new technologies intensify exploitation and deepen both labour and spatial marginalization

Gene replacement in mice reveals that the heavily phosphorylated tail of neurofilament heavy subunit does not affect axonal caliber or the transit of cargoes in slow axonal transport

The COOH-terminal tail of mammalian neurofilament heavy subunit (NF-H), the largest neurofilament subunit, contains 44-51 lysine–serine–proline repeats that are nearly stoichiometrically phosphorylated after assembly into neurofilaments in axons. Phosphorylation of these repeats has been implicated in promotion of radial growth of axons, control of nearest neighbor distances between neurofilaments or from neurofilaments to other structural components in axons, and as a determinant of slow axonal transport. These roles have now been tested through analysis of mice in which the NF-H gene was replaced by one deleted in the NF-H tail. Loss of the NF-H tail and all of its phosphorylation sites does not affect the number of neurofilaments, alter the ratios of the three neurofilament subunits, or affect the number of microtubules in axons. Additionally, it does not reduce interfilament spacing of most neurofilaments, the speed of action potential propagation, or mature cross-sectional areas of large motor or sensory axons, although its absence slows the speed of acquisition of normal diameters. Most surprisingly, at least in optic nerve axons, loss of the NF-H tail does not affect the rate of transport of neurofilament subunits

Induction of Autophagy by Cystatin C: A Mechanism That Protects Murine Primary Cortical Neurons and Neuronal Cell Lines

Cystatin C (CysC) expression in the brain is elevated in human patients with epilepsy, in animal models of neurodegenerative conditions, and in response to injury, but whether up-regulated CysC expression is a manifestation of neurodegeneration or a cellular repair response is not understood. This study demonstrates that human CysC is neuroprotective in cultures exposed to cytotoxic challenges, including nutritional-deprivation, colchicine, staurosporine, and oxidative stress. While CysC is a cysteine protease inhibitor, cathepsin B inhibition was not required for the neuroprotective action of CysC. Cells responded to CysC by inducing fully functional autophagy via the mTOR pathway, leading to enhanced proteolytic clearance of autophagy substrates by lysosomes. Neuroprotective effects of CysC were prevented by inhibiting autophagy with beclin 1 siRNA or 3-methyladenine. Our findings show that CysC plays a protective role under conditions of neuronal challenge by inducing autophagy via mTOR inhibition and are consistent with CysC being neuroprotective in neurodegenerative diseases. Thus, modulation of CysC expression has therapeutic implications for stroke, Alzheimer's disease, and other neurodegenerative disorders

Myosin Va binding to neurofilaments is essential for correct myosin Va distribution and transport and neurofilament density

The identification of molecular motors that modulate the neuronal cytoskeleton has been elusive. Here, we show that a molecular motor protein, myosin Va, is present in high proportions in the cytoskeleton of mouse CNS and peripheral nerves. Immunoelectron microscopy, coimmunoprecipitation, and blot overlay analyses demonstrate that myosin Va in axons associates with neurofilaments, and that the NF-L subunit is its major ligand. A physiological association is indicated by observations that the level of myosin Va is reduced in axons of NF-L–null mice lacking neurofilaments and increased in mice overexpressing NF-L, but unchanged in NF-H–null mice. In vivo pulse-labeled myosin Va advances along axons at slow transport rates overlapping with those of neurofilament proteins and actin, both of which coimmunoprecipitate with myosin Va. Eliminating neurofilaments from mice selectively accelerates myosin Va translocation and redistributes myosin Va to the actin-rich subaxolemma and membranous organelles. Finally, peripheral axons of dilute-lethal mice, lacking functional myosin Va, display selectively increased neurofilament number and levels of neurofilament proteins without altering axon caliber. These results identify myosin Va as a neurofilament-associated protein, and show that this association is essential to establish the normal distribution, axonal transport, and content of myosin Va, and the proper numbers of neurofilaments in axons

Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing.

Neurodegenerative disorders of ageing (NDAs) such as Alzheimer disease, Parkinson disease, frontotemporal dementia, Huntington disease and amyotrophic lateral sclerosis represent a major socio-economic challenge in view of their high prevalence yet poor treatment. They are often called 'proteinopathies' owing to the presence of misfolded and aggregated proteins that lose their physiological roles and acquire neurotoxic properties. One reason underlying the accumulation and spread of oligomeric forms of neurotoxic proteins is insufficient clearance by the autophagic-lysosomal network. Several other clearance pathways are also compromised in NDAs: chaperone-mediated autophagy, the ubiquitin-proteasome system, extracellular clearance by proteases and extrusion into the circulation via the blood-brain barrier and glymphatic system. This article focuses on emerging mechanisms for promoting the clearance of neurotoxic proteins, a strategy that may curtail the onset and slow the progression of NDAs