Tau misfolding and assembly is linked to a number of neurodegenerative diseases collectively described as tauopathies, including Alzheimer’s disease (AD) and Parkinson’s disease. Anionic cellular membranes, such as the cytosolic leaflet of the plasma membrane, are sites that concentrate and neutralize tau, primarily due to electrostatic interactions with tau’s microtubule binding repeat domain (RD). In addition to electrostatic interactions with lipids, tau also has interactions with membrane proteins, which are important for tau’s cellular functions. Tau also interacts with lipid tails to facilitate direct translocation across the membrane and can form stable protein-lipid complexes involved in cell-to-cell transport. Concentrated tau monomers at the membrane surface can form reversible condensates, change secondary structures, and induce oligomers, which may eventually undergo irreversible crosslinking and fibril formation. These β-sheet rich tau structures are capable of disrupting membrane organization and are toxic in cell-based assays. Given the evidence for relevant membrane-based tau assembly, we review the emerging hypothesis that polyanionic membranes may serve as a site for phase-separated tau condensation. Membrane-mediated phase separation may have important implications for regulating tau folding/misfolding, and may be a powerful mechanism to spatially direct tau for native membrane-mediated functions.

The Endocannabinoid System Structure and FunctionWith all the complex cell signals, genetic mutations, and outside influences, how do we manage to stay at homeostasis? The answer is the endocannabinoid system. It is present nearly everywhere in the human body and functions by maintaining the homeostasis of the human body (Alger, 2013). This is achieved through a negative feedback loop which works by the activation of a postsynaptic neuron synthesizing and releasing the endocannabinoids as they target various cannabinoid (CB) receptors.These CB receptors are G-protein-coupled receptors (Gambi et al., 2005), which allow them to directly influence the incoming signals. This functions as an "override" signal, which differs from most other cells. As other cells have signal modifiers that can do anything from amplifying to diverging signals, the neuron is "over-riding" those cells. For example, a fracture in the toe would result in cell death. The resulting lymphatic response would increase blood flow and the migration of white blood cells to the surrounding areas. The ECS would then recognize the excess lymphatic signals, and after deciding that there is no longer a need for the increase of inflammation, the CB receptors in the surrounding immune cells and tissues will begin to bind with cannabinoids and start to slowly reduce these inflammatory responses.A similar process occurs with pain signals in the brain. The binding and stimulation of CB1 receptors will upregulate the gamma-aminobutyric acid (GABA) neurotransmitters, thereby reducing pain signals throughout the brain. There are two main receptors in the ECS: the CB1 and CB2 receptors. CB1 receptors are located primarily within brain cells (including but not limited to the hippocampus, amygdala, and hypothalamus), and are not as densely expressed in the CNS, PNS, and the immune system. On the other hand, the CB2 receptors are located primarily in the CNS, PNS, immune system, and within white blood cells. Additionally, the existence of CB3 receptors is also hypothesized (Iqbal, 2007). TheseThe endocannabinoid system (ECS) plays a very important role in the human body for our survival. This is due to its ability to play a critical role in maintaining the homeostasis of the human body, which encompasses the brain, endocrine, and immune system, to name a few. ECS is a unique system in multiple dimensions. To begin with, it is a retrograde system functioning post-to pre-synapse, allowing it to be a "master regulator" in the body. Secondly, it has a very wide scope of influence due to an abundance of cannabinoid receptors located anywhere from immune cells to neurons. Finally, cannabinoids are rapidly synthesized and degraded, so they do not stay in the body for very long in high amounts, possibly enabling cannabinoid therapy to be a safer alternative to opioids or benzodiazepines. This paper will discuss how ECS functions through the regulation of neurotransmitter function, apoptosis, mitochondrial function, and ion-gated channels. The practical applications of the ...