71 Matching Annotations
  1. Dec 2017
    1. Hippocampal theta and gamma oscillations and cross-frequency coupling (CFC) through theta-phase modulation of gamma power are measures of network activity related to memory, including in humans

      Phase amplitude coupling measures the coupling between theta and gamma waves in the hippocampus. The theta and gamma waves are associated with learning and memory. Figure I shows virtually no phase amplitude frequency in the mice with Alz compared to Alz free mice, especially in the APP23p38𝛾-/- mice. Such low frequencies would suggest those mice would have the most problems with learning and memory.


    2. a phosphorylation-mimicking Thr205→Glu205 (T205E) tau variant coprecipitated significantly less with PSD-95 as compared with nonmutant and T205A (A, Ala) tau (Fig. 4C and fig. S21)

      Phosphorylation at T205 inhibits complex formation.

    3. T205 phosphorylation of tau is part of an Aβ toxicity–inhibiting response.

      Phosphorylation at T205 on tau limits Amyloid beta toxicity.

    4. PSD-95/tau/Fyn

      Researchers have found the binding of tau and fyn have been associated with Alzheimer’s disease pathology. Fyn is a kinase that phosphorylates tau and co-localizes with tau in the neurons of Alzheimer’s patients with tau tangles. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4870772/

    5. Aβ is thought to trigger toxic events, including tau phosphorylation

      E. S. Musiek, D. M. Holtzman, Nat. Neurosci. 18, 800–806 (2015). Amyloid-beta is a key initiator of all the downstream processes that cause Alzheimer’s. One process Aβ leads to is initiating tau tangles. Even though Aβ is a key player, Aβ can not cause Alzheimer’s by itself.

    6. Aberrant tau phosphorylation is the first step in a cascade leading to its deposition and to cognitive dysfunction

      K. Iqbal, F. Liu, C.-X. Gong, A del C. Alonso, I. Grundke-Iqbal, Acta Neuropathol. 118, 53–69 (2009). Neurodegeneration from tau implications can be caused from different protein kinases hyperphosphorylating tau. Hyperphosphorylated tau can misfold, create tangles, and not able to stabilize microtubules, all which can all lead to loss of connectivity between neurons.

    7. APP23 mice present with premature mortality, memory deficits, neuronal circuit aberrations with epileptiform brain activity, and Aβ pathology

      L. M. Ittner et al., Cell 142, 387–397 (2010)

      APP23 mice have increased Aβ toxicity which is the main contributor to the deficits seen in APP23 mice. Deficits include premature death, increased Aβ at young ages, decreased memory, and irregular neuronal circuits.

    8. p38γ regulated PSD-95/tau/Fyn complexes, likely at the level of PSD-95/tau interaction

      From Fig. 3 the authors conclude that p38y reduces PSD-95/tau/Fyn complex formation by affecting PSD-95/Fyn interactions.

    9. PTZ transiently increased PSD-95/tau/Fyn complex formation in p38γ+/+ animals; this effect was even more noticeable in p38γ−/− mice

      p38y was shown to inhibit the formation of complexes, but the addition of PTZ lowers the protective function of p38y.

    10. PSD-95/tau/Fyn interaction was reduced in transgenic mice with neuronal expression of p38γCA

      The interactions that are required to form the complexes are reduced in mice with an active form of p38y, demonstrating that p38y may prevent complex formation.

    11. PSD-95 copurified more tau and Fyn from p38γ−/− versus p38γ+/+ brains, and even more from APP23.p38γ−/− compared with APP23.p38γ+/+ and p38γ−/− brains

      An immunoprecipitation for PSD-95 was ran. The proteins that were associated with PSD-95 complexes also precipitated due being in a complex with PSD-95. The results show that tau and Fyn were contributing more to the PSD-95 complexes when p38y was not present.

    12. PSD-95/tau/Fyn interaction was enhanced in Alz17.p38γ−/− animals versus Alz17.p38γ+/+ mice

      Results show that more PSD-95/tau/Fyn complexes were in the brains of p38𝛾-/- vs. p38𝛾+/+. This shows that PSD-95/tau/Fyn complexes are associated Amyloid-beta induced excitotoxicity

    13. when compared to tau−/−.p38γ+/+mice, tau−/−.p38γ−/− animals showed similar protection from PTZ-induced seizures

      p38y only protects agianst PTZ-induce siezures only when tau is present. A difference between p38y being present and p38 being absent is only seen in mice that have tau.

    14. These data also showed that, compared with APP23 mice, APP23.p38γ−/− animals had aggravated memory deficits that persisted with aging

      APP23.p38y+/+ mice survived longer and had performed better in water maze than APP23.p38y-/- mice. Also shown in the results is that APP23.p38y+/+.tau-/- vs. APP23.p38y-/-tau-/- mice, are statistically the same, suggesting that the protective effect of p38 comes from phosphorylating tau.

    15. The exacerbating effects of p38γ loss on reduced survival, memory deficits, and neuronal network dysfunction of APP23 mice were virtually abolished in APP23.p38γ−/−.tau−/− mice

      The APP23 deficits improved when tau was not present in mice.

    16. To determine whether the Aβ toxicity–limiting effects of p38γ were tau-dependent, we crossed APP23.p38γ−/− with tau−/− mice.

      The basic question for Fig. 2: Is the protective effect that p38y has against Amyloid beta toxicity only seen in mice that have tau proteins. Experiments were ran on mice that had various combinations of p38y and tau.

    17.  p38γ−/− mice showed no deficits and had normal motor function

      The lack of p38y kinase did not negatively affect the movement and motor function of the mice.

    18. N-methyl-D-aspartate (NMDA)–type glutamatergic receptors (NRs) drive glutamate-induced neuronal excitotoxicity

      Hardingham and Bading show that NMDAR responses depend on receptor location. Synaptic NMDARs promotes cell survival, while stimulation of extrasynaptic NMDARs promotes cell death. The unequal stimulation of these receptors cause neuronal dysfunction, while stimulation of synaptic receptors could be used a protective therapy.

    19. Aβ pathology was comparable in the brains of APP23.p38γ−/− and APP23.p38γ+/+ mice (fig. S6), but p38γ deletion aggravated premature mortality and memory deficits of APP23 mice

      APP23 mice that had p38y and did not have p38y displayed similar traits, but the deficits in mice that did not possess p38y kinase were worse.

    20. To test whether p38γ−/− augments Aβ-induced deficits, we crossed p38γ−/− with Aβ-forming APP23 mice.

      Fig 1 C-J experiments are testing to see if the abscence of p38y increases amyloid beta deficiets. Mice that have amyloid beta deficets were bred with mice that did not have p38y kinase. Amyloid beta - forming APP23 mice have amyloid beta induced deficits.

    21. escape latency

      time elapsed between start and completion of the morris water maze

    22. Surprisingly, only p38γ depletion (p38γ−/−), but not systemic p38β, p38δ, or neuronal p38α (p38αΔneu) knockout, changed PTZ-induced seizures

      The only knockout mouse that displayed a change associated with PTZ-seizures was p38y. Because p38y was the only one that influenced the results, it is the focus of all the experiments.

    23. We used mice with individual deletion of p38α, p38β, p38γ, or p38δ

      Each mouse had one isoform of the p38 kinase eliminated from its cellular biology. All other forms are present.

    24. To understand the roles of p38 kinases in AD, we induced excitotoxic seizures with pentylenetetrazole (PTZ), an approach widely used for studying excitotoxicity in AD mouse models

      The basic goal of the research was to understand the role of p38 kinases in AD mice. The experiment used mice that were made to have excitotoxic seizures through injection of pentylenetetrazole (PTZ). Injection of PTZ has been used in the past to study excitotoxicity in AD mice models.

    25. Aβ precursor protein (APP)

      Amyloid beta precursor protein (APP); The protein is found in many tissues and concentrated at the synapses of neurons.The protein itself is not dangerous, it is found in many tissues and concentrated at the synapses of neurons. Truncated forms of APP can form plaques that cause AB toxicity.

    26.  N-methyl-D-aspartate (NMDA)–type glutamatergic receptors

      Receptor and ion channel protein found in neurons, which controls the ability of synapses to weaken or strengthen due to brain activity level and memory function.

    27. p38γ

      A kinase that helps transfer a phosphate group to a specific site on the tau protein. Each isoform of the p38 kinase phosphorylates tau at a different site. A kinase is a protein that catalyzes the transfer of a phosphate group to a specific site on a specific protein.

    28. Alzheimer’s disease (AD)

      Alzheimer’s disease is a brain disorder that worsens with age and has no known cure. The disease affects different aspects of cognition and memory, and can eventually lead to shutdown of the body. https://www.youtube.com/watch?v=fT7UovfLl8c

    29. Amyloid-β (Aβ) toxicity

      Amyloid beta is a short chain amino acid and is a main component of amyloid plaques that are associated with Alzheimer’s. Amyloid beta plaques are located outside of neurons. Amyloid beta plaques are composed of amyloid precursor protein (APP) that is truncated into a shorter form. Amyloid beta toxicity occurs when the build of of amyloid beta plaques becomes toxic to neural cells.

    30. APP23

      APP23 is a version of APP that will develop into AB plaques and aggregates that are associated with Alzheimer’s disease. The APP23 mouse in the experiment overexpressed the APP23 protein.

      Previous work: Animals can produce amyloid-beta independently of using APP precursor protein. However, when animals have APP23 mutation, the APP is overexpressed and amyloid beta plaques and intracellular amyloid beta aggregates form. The APP23 has been linked to synapse loss and dendrite degeneration. The APP23 is a Swedish mutation in CNS neurons. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4046770/ )

    31. Pan-p38 inhibition stopped p38γ/p38γCA-induced disruption of PSD-95/tau/Fyn complexes

      If p38y is completely inhibited, the complexes are stable.

    32. Increasing p38γ levels compromised PSD-95/tau/Fyn interaction in cells, and expression of a constitutively active p38γ variant (p38γCA) completely abolished this interaction

      p38y was shown to prevent the interactions required to form the complexes associated.

    33. no PSD-95/tau/Fyn complexes were isolated from tau−/− and tau−/−.p38γ−/− brains

      Demonstrates that the complexes will not form if unless tau is present.

    34. We have previously shown that postsynaptic PSD-95/tau/Fyn complexes mediate Aβ-induced excitotoxicity

      L. M. Ittner et al., Cell 142, 387–397 (2010).: In this article, Ittner and others show that the absence of tau in amyloid beta-forming mice lessens the severity of amyloid beta toxicity. These results suggest that tau and amyloid beta together increases the symptoms and progression of Alzheimer’s disease.

    35. the effects of p38γ on excitotoxicity and Aβ toxicity were tau-dependent.

      The protective qualities of p38y are dependent on tau being present. If tau is not present, amyloid-beta toxicity effects the cells the same, even if p38y is present.

    36. increasing tau levels in p38γ−/− mice [brought about by crossing with nonmutant tau-expressing Alz17 mice (23)] significantly enhanced PTZ-induced seizures in Alz17.p38γ−/− mice

      Mice that had higher levels of tau were more susceptible to seizures.

    37. In summary, p38γ depletion exacerbated excitotoxicity, neuronal circuit synchronicity, mortality, and memory deficits in APP23 mice, without changes in Aβ pathology.

      Overall, every deficit associated with APP23 was made worse when p38y was not present.

    38. Compromised spectral power and CFC of APP23.p38γ+/+ mice were significantly more affected in APP23.p38γ−/− recordings

      Is this saying that the memory of APP23 p38 negative mice is worse or that APP23 p38 mice memories are worse?

    39. Electroencephalography showed enhanced spontaneous epileptiform activity and interictal hypersynchronous discharges in APP23.p38γ−/− compared with APP23.p38γ+/+ mice

      From the results, the researchers can infer that the presence of p38𝛾 kinase has a protective ability that lessens the amount of seizure trains that occur due to Aβ density bodies

    40. Compared with APP23.p38γ+/+ mice, APP23.p38γ−/− animals had increased sensitivity to PTZ-induced seizures

      From the results conducted in the experiment, specifically the Fig. 1 G-J, mice that did not possess p38y were more sensitive to seizures

    41. only p38γ localized to postsynapses and limited excitotoxicity.

      The only knockout mouse that was shown to cause a change in PTZ-induced seizures was p38𝛾. p38𝛾 was also the only kinase that was shown to localize in postsynapses between neurons.

    42. Morris water maze (MWM) test:

      Mice are placed in a circular pool of water. In one of the quadrants, a hidden platform is present. The platform allows the mice to stand instead of swim.The mice are shown where the platform is and how to get to it multiple times. After showing the mice, the researchers put the mice somewhere in the four quadrants and track their movement as the mice attempt to find the platform. Time to escape can also be quantified. (https://www.jove.com/video/2920/morris-water-maze-test-for-learning-memory-deficits-alzheimers)

    43. tau

      Tau is a protein that stabilizes microtubular cytoplasmic components in neurons.

    44. Immunoprecipitation (IP) analysis

      A technique to find protein-protein complexes by precipitating an antigen protein from a solution using an antibody that binds to a particular antigen from a sample.

    45. spike frequency

      response of a neuron to a stimulus

    46. spike train

      electrical signals recorded from individual neurons

    47. downstream

      after the initial step

    48. interictal

      the time between seizures

    49. modulation

      change or variation

    50. phosphorylation

      to add an inorganic phosphate group to a substance, usually to affect the activity of the substance

    51. systemic 

      completely; throughout

    52. Mortality


    53. oscillations

      to move up and down on a scale

    54. Fyn

      A protein that phosphorylates Tau and is involved in neuronal growth.

    55. epileptiform

      A wave on an EEG that is a sharp wave or spike that is a marker for patients with epilepsy or a focus of seizure studies.

    56. Electroencephalography

      Electroencephalography (EEG), measures electrical activity of the brain Epileptiform: A wave on an EEG that is a sharp wave or spike that is a marker for patients with epilepsy or a focus of seizure studies.

    57. exacerbated

      to aggravate, make a situation worse

    58. augmented

      to amplify, make greater in size or value

    59. PTZ

      Pentylenetetrazole, a central nervous system (CNS) stimulant used to assess the excitability of the CNS. The drug is administered and 30 minutes after, seizure profiles are examined.

    60. excitotoxicity

      The death or damage of nerve cells by over stimulation by neurotransmitters.

    61. aberrations

      A deviation from the normal type behavior

  2. Nov 2017
    1. p38 kinases

      Kinases are proteins that help move phosphate groups from one protein to another. p38 kinase phosphorylates tau and each form phosphorylates at a different site.

    2. mimicking site-specific tau phosphorylation alleviated Aβ-induced neuronal death and offered protection from excitotoxicity.

      The site that is phosphorylated by p38y was found to be important for reducing effects of AD. Demonstrates that the function of p38y is important, and the mere presence of p38y in the cell is not protective, it has to be functional.

    3. depletion of p38γ exacerbated neuronal circuit aberrations, cognitive deficits, and premature lethality in a mouse model of AD, whereas increasing the activity of p38γ abolished these deficits

      The research found that the presence of p38y reduced the effects of AD in the mouse model.

    1. it in-creases hyperexcitability in Abprecursor protein(APP) transgenic mice

      Side effects of phosphorylation

    2. n-hibition of p38aand p38bimproves Ab-induced

      inhibition may have a short term positive effect

    3. ong-term potentiation deficits

      memory formation deficits or ability to retain memories deficit

    4. Accordingly, the depletion of tau prevents Abtoxicity in AD models (7–9). Ab-induced neuronalnetwork and synaptic dysfunction is associatedwith aberrant glutamatergic synaptic transmis-sion (10).N-methyl-D-aspartate (NMDA)–typeglutamatergic receptors (NRs) drive glutamate-induced neuronal excitotoxicity (11)andmediateAbtoxicity by downstream responses that pro-mote neuronal dysfunction (12

      The steps that tau tangles interfere with in the transmittance of signals in the brain.

    5. Aberrant tau phosphorylation is the firststep in a cascade leading to its deposition and tocognitive dysfunction (4,5). Abis thought to trig-ger toxic events, including tau phosphorylation

      steps and relevance to Alzheimer's disea

    6. Alzheimer’s disease (AD), the most prevalentform of dementia, is neuropathologicallycharacterized by extracellular amyloid-b(Ab)plaques and intracellular tau-containingneurofibrillary tangles

      Definition of Alzheimer's

    7. importance