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Dynamic gain and loss of synapses is fundamental to healthy brain function. While Alzheimer’s Disease (AD) treatment strategies have largely focussed on beta-amyloid and tau protein pathologies, the synapse itself may also be a critical endpoint to consider regarding disease modification. Disruption of mechanisms of neuronal plasticity, eventually resulting in a net loss of synapses, is implicated as an early pathological event in AD. Synaptic dysfunction therefore may be a final common biological mechanism linking protein pathologies to disease symptoms. This review summarizes evidence supporting the idea of early neuroplastic deficits being prevalent in AD. Changes in synaptic density can occur before overt neurodegeneration and should not be considered to uniformly decrease over the course of the disease. Instead, synaptic levels are influenced by an interplay between processes of degeneration and atrophy, and those of maintenance and compensation at regional and network levels. How these neuroplastic changes are driven by amyloid and tau pathology are varied. A mixture of direct effects of amyloid and tau on synaptic integrity, as well as indirect effects on processes such as inflammation and neuronal energetics are likely to be at play here. Focussing on the synapse and mechanisms of neuroplasticity as therapeutic opportunities in AD raises some important conceptual and strategic issues regarding translational research, and how preclinical research can inform clinical studies. Nevertheless, substrates of neuroplasticity represent an emerging complementary class of drug target that would aim to normalize synapse dynamics and restore cognitive function in the AD brain and in other neurodegenerative diseases.

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U-500 insulin is efficacious and safe for patients with type 2 diabetes who require a high dosage of insulin to control hyperglycemia. However, health care professionals should be well educated and vigilant about patient safety issues regarding the drug's prescription, dosing, and administration.

To what extent, how and when axons respond to injury in the highly interconnected grey matter is poorly understood. Here we use two-photon imaging and focused ion beamscanning electron microscopy to explore, at synaptic resolution, the regrowth capacity of several neuronal populations in the intact brain. Time-lapse analysis of 4100 individually ablated axons for periods of up to a year reveals a surprising inability to regenerate even in a glial scar-free environment. However, depending on cell type some axons spontaneously extend for distances unseen in the unlesioned adult cortex and at maximum speeds comparable to peripheral nerve regeneration. Regrowth follows a distinct pattern from developmental axon growth. Remarkably, although never reconnecting to the original targets, axons consistently form new boutons at comparable prelesion synaptic densities, implying the existence of intrinsic homeostatic programmes, which regulate synaptic numbers on regenerating axons. Our results may help guide future clinical investigations to promote functional axon regeneration.

IntroductionThis study aimed to determine the homing potential and fate of epidermal neural crest stem cells (eNCSCs) derived from hair follicles, and bone marrow-derived stem cells (BMSCs) of mesenchymal origin, in a lipopolysaccharide (LPS)-induced inflammatory lesion model in the rat brain. Both eNCSCs and BMSCs are easily accessible from adult tissues by using minimally invasive procedures and can differentiate into a variety of neuroglial lineages. Thus, these cells have the potential to be used in autologous cell-replacement therapies, minimizing immune rejection, and engineered to secrete a variety of molecules.MethodsBoth eNCSCs and BMSCs were prelabeled with iron-oxide nanoparticles (IO-TAT-FITC) and implanted either onto the corpus callosum in healthy or LPS-lesioned animals or intravenously into lesioned animals. Both cell types were tracked longitudinally in vivo by using magnetic resonance imaging (MRI) for up to 30 days and confirmed by postmortem immunohistochemistry.ResultsTransplanted cells in nonlesioned animals remained localized along the corpus callosum. Cells implanted distally from an LPS lesion (either intracerebrally or intravenously) migrated only toward the lesion, as seen by the localized MRI signal void. Fluorescence microscopy of the FITC tag on the nanoparticles confirmed the in vivo MRI data,ConclusionsThis study demonstrated that both cell types can be tracked in vivo by using noninvasive MRI and have pathotropic properties toward an inflammatory lesion in the brain. As these cells differentiate into the glial phenotype and are derived from adult tissues, they offer a viable alternative autologous stem cell source and gene-targeting potential for neurodegenerative and demyelinating pathologies.

OBJECTIVEHuman regular U-500 (U-500R) insulin (500 units/mL) is increasingly being used clinically, yet its pharmacokinetics (PK) and pharmacodynamics (PD) have not been well studied. Therefore, we compared PK and PD of clinically relevant doses of U-500R with the same doses of human regular U-100 (U-100R) insulin (100 units/mL).RESEARCH DESIGN AND METHODSThis was a single-site, randomized, double-blind, crossover euglycemic clamp study. Single subcutaneous injections of 50- and 100-unit doses of U-500R and U-100R were administered to 24 healthy obese subjects.RESULTSBoth overall insulin exposure (area under the serum insulin concentration versus time curve from zero to return to baseline [AUC0-t’]) and overall effect (total glucose infused during a clamp) were similar between formulations at both 50- and 100-unit doses (90% [CI] of ratios contained within [0.80, 1.25]). However, peak concentration and effect were significantly lower for U-500R at both doses (P < 0.05). Both formulations produced relatively long durations of action (18.3 to 21.5 h). Time-to-peak concentration and time to maximum effect were significantly longer for U-500R than U-100R at the 100-unit dose (P < 0.05). Time variables reflective of duration of action (late tRmax50, tRlast) were prolonged for U-500R versus U-100R at both doses (P < 0.05).CONCLUSIONSOverall exposure to and action of U-500R insulin after subcutaneous injection were no different from those of U-100R insulin. For U-500R, peaks of concentration and action profiles were blunted and the effect after the peak was prolonged. These findings may help guide therapy with U-500R insulin for highly insulin-resistant patients with diabetes.

SummarySynapse loss is a key feature of dementia, but it is unclear whether synaptic dysfunction precedes degenerative phases of the disease. Here, we show that even before any decrease in synapse density, there is abnormal turnover of cortical axonal boutons and dendritic spines in a mouse model of tauopathy-associated dementia. Strikingly, tauopathy drives a mismatch in synapse turnover; postsynaptic spines turn over more rapidly, whereas presynaptic boutons are stabilized. This imbalance between pre- and post-synaptic stability coincides with reduced synaptically driven neuronal activity in pre-degenerative stages of the disease.