scholarly journals PAC1 receptor–mediated clearance of tau in postsynaptic compartments attenuates tau pathology in mouse brain

2021 ◽  
Vol 13 (595) ◽  
pp. eaba7394
Author(s):  
Ari W. Schaler ◽  
Avery M. Runyan ◽  
Catherine L. Clelland ◽  
Eric J. Sydney ◽  
Stephanie L. Fowler ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Brain Tissue ◽  
Mouse Brain ◽  
Subcellular Fractionation ◽  
Proteasome Activity ◽  
Postmortem Brain ◽  
Early Event ◽  
Pac1 Receptor ◽  
Human Postmortem Brain ◽  
Postmortem Brain Tissue

Accumulation of pathological tau in synapses has been identified as an early event in Alzheimer’s disease (AD) and correlates with cognitive decline in patients with AD. Tau is a cytosolic axonal protein, but under disease conditions, tau accumulates in postsynaptic compartments and presynaptic terminals, due to missorting within neurons, transsynaptic transfer between neurons, or a failure of clearance pathways. Using subcellular fractionation of brain tissue from rTg4510 tau transgenic mice with tauopathy and human postmortem brain tissue from patients with AD, we found accumulation of seed-competent tau predominantly in postsynaptic compartments. Tau-mediated toxicity in postsynaptic compartments was exacerbated by impaired proteasome activity detected by measuring lysine-48 polyubiquitination of proteins targeted for proteasomal degradation. To combat the accumulation of tau and proteasome impairment in the postsynaptic compartments of rTg4510 mouse brain, we stimulated the pituitary adenylate cyclase–activating polypeptide (PACAP) type 1 receptor (PAC1R) with its ligand PACAP administered intracerebroventricularly to rTg4510 mice. We observed enhanced synaptic proteasome activity and reduced total tau in postsynaptic compartments in mouse brain after PACAP treatment. The clearance of tau from postsynaptic compartments correlated with attenuated tauopathy and improved cognitive performance of rTg4510 transgenic mice on two behavioral tests. These results suggest that activating PAC1R could prevent accumulation of aggregate-prone tau and indicate a potential therapeutic approach for AD and other tauopathies.

Cells in human postmortem brain tissue slices remain alive for several weeks in culture

2002 ◽  
Vol 16 (1) ◽  
pp. 54-60 ◽  
Author(s):  
Ronald W. H. Verwer ◽  
Wim T. J. M. C. Hermens ◽  
Paul A. Dijkhuizen ◽  
Olivier Ter Brake ◽  
Robert E. Baker ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Postmortem Brain ◽  
Tissue Slices ◽  
Human Postmortem Brain ◽  
Postmortem Brain Tissue

scholarly journals Activity of the poly(A) binding protein MSUT2 determines susceptibility to pathological tau in the mammalian brain

2019 ◽  
Vol 11 (523) ◽  
pp. eaao6545 ◽  
Author(s):  
Jeanna M. Wheeler ◽  
Pamela McMillan ◽  
Timothy J. Strovas ◽  
Nicole F. Liachko ◽  
Alexandre Amlie-Wolf ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Brain Tissue ◽  
Rna Binding ◽  
Binding Protein ◽  
Disease Onset ◽  
Tail Length ◽  
Postmortem Brain ◽  
Mammalian Brain ◽  
Macromolecular Complex ◽  
Postmortem Brain Tissue

Brain lesions composed of pathological tau help to drive neurodegeneration in Alzheimer’s disease (AD) and related tauopathies. Here, we identified the mammalian suppressor of tauopathy 2 (MSUT2) gene as a modifier of susceptibility to tau toxicity in two mouse models of tauopathy. Transgenic PS19 mice overexpressing tau, a model of AD, and lacking the Msut2 gene exhibited decreased learning and memory deficits, reduced neurodegeneration, and reduced accumulation of pathological tau compared to PS19 tau transgenic mice expressing Msut2. Conversely, Msut2 overexpression in 4RTauTg2652 tau transgenic mice increased pathological tau deposition and promoted the neuroinflammatory response to pathological tau. MSUT2 is a poly(A) RNA binding protein that antagonizes the canonical nuclear poly(A) binding protein PABPN1. In individuals with AD, MSUT2 abundance in postmortem brain tissue predicted an earlier age of disease onset. Postmortem AD brain tissue samples with normal amounts of MSUT2 showed elevated neuroinflammation associated with tau pathology. We observed co-depletion of MSUT2 and PABPN1 in postmortem brain samples from a subset of AD cases with higher tau burden and increased neuronal loss. This suggested that MSUT2 and PABPN1 may act together in a macromolecular complex bound to poly(A) RNA. Although MSUT2 and PABPN1 had opposing effects on both tau aggregation and poly(A) RNA tail length, we found that increased poly(A) tail length did not ameliorate tauopathy, implicating other functions of the MSUT2/PABPN1 complex in tau proteostasis. Our findings implicate poly(A) RNA binding proteins both as modulators of pathological tau toxicity in AD and as potential molecular targets for interventions to slow neurodegeneration in tauopathies.

Tract tracing, neuronal morphology and ultrastructural studies in human postmortem brain

1992 ◽  
Vol 50 (1) ◽  
pp. 470-471
Author(s):  
Rosalinda C. Roberts ◽  
Michael W. Vogel ◽  
Maarten de Rijk ◽  
Frank J. Peretti ◽  
Robert R. Conley ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Neuronal Morphology ◽  
Postmortem Brain ◽  
Human Brain Tissue ◽  
Tract Tracing ◽  
Human Postmortem Brain ◽  
Ultrastructural Studies ◽  
Carbocyanine Dye ◽  
Postmortem Brain Tissue ◽  
Golgi Staining

Classical and modern neuroanatomical techniques are applied to an analysis of the neuroanatomical basis of schizophrenia using postmortem brain tissue from the Maryland Brain Collection. Techniques for Golgi staining of cell bodies and dendritic arbors, axonal tract tracing with the carbocyanine dye, DiI and ultrastructural analyses will be used to study brain tissue with postmortem times of less than 6 hours. Although these techniques are routinely used in animal models, they are rarely used for studying human brain tissue. These techniques will allow us to characterize neuronal architecture in normal and diseased brains.

scholarly journals Tryptophan is a marker of human postmortem brain tissue quality

2009 ◽  
Vol 110 (5) ◽  
pp. 1400-1408 ◽  
Author(s):  
Edna Grünblatt ◽  
Camelia Maria Monoranu ◽  
Manuela Apfelbacher ◽  
Daniela Keller ◽  
Tanja M. Michel ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Postmortem Brain ◽  
Tissue Quality ◽  
Human Postmortem Brain ◽  
Postmortem Brain Tissue
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