promote neuronal dysfunction (12).
Amyloid beta accumulation creates synaptic impairment and learning and memory deficits in AD patients. The impairment of neurons as opposed to neuronal loss maybe the mechanism behind cognitive impairment in AD patients. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385944/)
Aβ toxicity
Blood test identifies key Alzheimer’s marker (https://www.sciencedaily.com/releases/2017/07/170719084821.htm) This article looks into how amyloid-beta levels can be tested. Currently our options are to use PET scans or do a spinal tap of CSF to test for amyloid-beta plaque presence. However, this study has found that a simple blood test has an 89% accuracy of telling use whether a person has any plaques in their brain or blood. Amyloid-beta has different subtypes of varying amino acid lengths, 38, 40, and 42. Amyloid plaques are mainly composed of 42 and 42 was found in the lowest level in the blood amongst the three, meaning the amyloid 42 is deposited into the brain before moving into the blood. The tests that came back positive from patients were confirmed by PET scans and spinal taps. Having a blood test to test the presence of amyloid plaques allows us to better see who is at risk for developing AD and possibly diagnose them years before symptoms appear, giving time for preventive care and treatment before the disease progresses.
Coexpression of p38γ or p38γCA and tau in cells revealed tau phosphorylation (p) at T205, less at S199, and hardly any at S396 or S404 (Fig. 4A)
This immunoprecipitations shows that in the presence of tau, p38𝛾 phosphorylates T205.
rescued memory deficits and network aberrations
Promising Alzheimer’s ‘drug’ halts memory loss (https://www.sciencedaily.com/releases/2013/06/130626184019.htm) I found this article interesting because it talked about p38 alpha. At the beginning of the article by Arne Ittner (2017) mice with depletion of p38 alpha, beta, gamma, and delta were all tested. Only p38 gamma depletion had an effect on PTZ seizures, so they tested p38𝛾 and its effect on mice with AD. This article from Northwestern University focuses on how p38 alpha becomes overactive in AD patients. Overactive p38 alpha leads to damage in the synapses by impairing glial cells protective abilities, disrupts the signal between neurons, and releases toxic molecules that can lead to more damage.
revealing an Aβ toxicity–limiting role of p38γ in AD
Discovery opens door to new Alzheimer’s treatments (https://www.sciencedaily.com/releases/2016/11/161117151205.htm) This article connected with our paper in many ways. Alzheimer’s patient have two things, protein plaques made from amyloid-beta, and tau tangles that are phosphorylated by the kinase. When tau is phosphorylated, it forms tangles. So we thought. What the study found is that when tau is initially phosphorylated, it is for protection. They focused on a protein kinase, p38𝛾, and found that is assists in phosphorylating tau and interferes with the amyloid-beta toxicity. When removed, Alzheimer's progresses. When reintroduced, it was therapeutic and helped halt Alzheimer’s progression.
However, this finding is in line with the idea that tau is involved in normal physiologic NR signaling events in neurons (12).
In normal physiological conditions tau is used to stabilize microtubular cytoplasmic components in neurons.
Finally, we found that tau-dependent Aβ toxicity was modulated by site-specific tau phosphorylation, which inhibited postsynaptic PSD-95/tau/Fyn complexes, revealing an Aβ toxicity–limiting role of p38γ in AD that is distinct and opposite to the effects of p38α and p38β (11, 13, 14).
The authors state, contrary to popular belief, that tau can play a protective role in limiting amyloid beta toxicity by interacting with p38γ. By phosphorylating specific sites tau can increase neuron survival and improve memory loss.
PTZ-induced seizures are reduced in tau−/− mice (8, 9). Adeno-associated virus (AAV)–mediated expression of WT and T205A neurons, but not T205E tau or green fluorescent protein (GFP), in the forebrains of tau−/− mice enhanced PTZ-induced seizures (Fig. 4D and fig. S25).
The data shows that the tau-/-.AAV tauWT and tau-/-.AAV tauT205A were the most susceptible to seizures and had the most severe seizures out of the four genotypes.
This is contrary to the current view that tau phosphorylation downstream of Aβ toxicity is a pathological response (3).
Ittner and Gӧtz review new findings showing the interactions of tau and amyloid beta. Tau can shift from the axon to the dendrite helping to increase amyloid beta toxicity.
Hence, phosphorylation of tau at T205 should similarly mitigate neurotoxicity. Aβ caused cell death in WT and T205A neurons but significantly less in T205E tau-expressing neurons (fig. S23). Similarly, neurons expressing p38γ and, more so, p38γCA were significantly more resistant to Aβ-induced cell death than controls (fig. S24).
The results from previous experiments showed that neurons survived at higher rates when they had T205E and p38γ.
Hence, p38γ regulated PSD-95/tau/Fyn complexes via phosphorylating tau at T205.
The results of this experiment showed that p38γ helped to disrupt the PSD-95/tau/Fyn complexes through phosphorylation of T205.
Similarly, T205 (and, less so, S199 and S396) were phosphorylated in p38γCA transgenic mice (fig. S19). pT205 increased after PTZ in p38γ+/+ animals but was virtually abolished in p38γ−/− mice, whereas pS199, pS396, and pS404 were induced in both p38γ+/+ and p38γ−/− mice (fig. S19).
This experiment wanted to see if the mutant sites were phosphorylated in the APP23.p38γ−/− and APP23.p38γ+/+ mice.
Similarly, pT205 was markedly reduced in APP23.p38γ−/− animals compared with APP23.p38γ+/+ mice (Fig. 4B)
The results of the previous experiment showed that APP23p38𝛾-/- mice had decreased T205 phosphorylation compared to the APP23p38𝛾+/+, which had T205 phosphorylation.
Although p38γ hyperphosphorylates tau during long-term in vitro kinase assays (25), the temporal profile of p38γ-induced tau phosphorylation in acute signaling remains unknown. Short-term in vitro kinase reactions using phosphorylation site–specific tau antibodies revealed phosphorylation at Ser199 (S199), Thr205 (T205), S396, and S404 (fig. S17). Mass spectrometric analysis confirmed these and 14 additional, though low-abundant, sites (figs. S17C and S18 and table S4).
The author set up different assays to test which variants were being phosphorylated by tau.
T205A
A mutant variant of T205 with the mutation in the phosphorylation site
T205E
A mutant variant of T205 that changes the site to act like a constitutively active phosphorylation site
In summary, the levels of active p38γ kinase and tau phosphorylation at T205 determined susceptibility to excitotoxicity and Aβ toxicity.
A. A. Ittner, A. Gladbach, J. Bertz, L. S. Suh, L. M. Ittner, p38 MAP kinase-mediated NMDA receptor-dependent suppression of hippocampal hypersynchronicity in a mouse model of Alzheimer’s disease. Acta Neuropathol. Commun. 2, 149 (2014).
In this study Ittner and others described the parts of the APP23 mouse model through artificial stimulation.
S. Li, M. Jin, T. Koeglsperger, N. E. Shepardson, G. M. Shankar, D. J. Selkoe, Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J. Neurosci. 31, 6627–6638 (2011).
Li and others studied how amyloid beta affects synaptic plasticity, or the ability of synapse to weaken or strengthen. The amyloid beta increases activation of extrasynaptic NMDARs.
Q. Wang, D. M. Walsh, M. J. Rowan, D. J. Selkoe, R. Anwyl, Block of long-term potentiation by naturally secreted and synthetic amyloid β-peptide in hippocampal slices is mediated via activation of the kinases c-Jun N-terminal kinase, cyclin-dependent kinase 5, and p38 mitogen-activated protein kinase as well as metabotropic glutamate receptor type 5. J. Neurosci. 24, 3370–3378 (2004).
Mucke and Selkoe show that amyloid beta binds to different parts of plasma membranes and induces neuronal dysfunction and disruption of networks.
L. M. Ittner, Y. D. Ke, F. Delerue, M. Bi, A. Gladbach, J. van Eersel, H. Wölfing, B. C. Chieng, M. J.Christie, I. A. Napier, A. Eckert, M. Staufenbiel, E. Hardeman, J. Götz, Dendritic function of tau mediates amyloid-β toxicity in Alzheimer’s disease mouse models. 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 increase the symptoms and progression of Alzheimer’s disease.
E. D. Roberson, K. Scearce-Levie, J. J. Palop, F. Yan, I. H. Cheng, T. Wu, H. Gerstein, G.-Q. Yu, L. Mucke, Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer’s disease mouse model. Science 316, 750–754 (2007).
Roberson and others conducted an experiment on mice to test targeting tau in Alzheimer’s as an effective treatment. The experiment showed that tau reduction can block amyloid beta neuronal dysfunction, showing that tau reduction could be a future effective treatment of Alzheimer’s.
L. M. Ittner, J. Götz, Amyloid-β and tau—a toxic pas de deux in Alzheimer’s disease. Nat. Rev. Neurosci. 12, 67–72 (2011).
Ittner and Gӧtz review new findings showing the interactions of tau and amyloid beta. Tau can shift from the axon to the dendrite helping to mediate amyloid beta toxicity.
C. Haass, D. J. Selkoe, Soluble protein oligomers in neurodegeneration: Lessons from the Alzheimer’s amyloid β-peptide. Nat. Rev. Mol. Cell Biol. 8, 101–112 (2007).
C. Haass, D. J. Selkoe,Nat. Rev. Mol. Cell Biol.8, 101–112(2007).: Haass and Selkoe show that in AD, small intermediates of amyloid beta, called oligomers, negatively affects synaptic structure and plasticity.
G. E. Hardingham, H. Bading, Synaptic versus extrasynaptic NMDA receptor signalling: Implications for neurodegenerative disorders. Nat. Rev. Neurosci. 11, 682–696 (2010).
Hardingham and Bading show that NMDAR responses depend on receptor location. Synaptic NMDARs promotes cell survival, while stimulate of extrasynaptic NMDARs promotes cell death. The unequal stimulation of these receptors neuronal dysfunction, while stimulation of synaptic receptors could be used a protective therapy.
C. Ballatore, V. M. Lee, J. Q. Trojanowski, Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat. Rev. Neurosci. 8, 663–672 (2007).
Ballatore, Lee, and Trojanowski review and summarize the recent discoveries of tau-mediated neurodegeneration mechanisms and how they can understand AD progression and discover new drug treatments.