Molecular Mechanisms for Neuronal Cell Death by Alzheimer’s Amyloid Precursor Protein-Relevant Insults

Neurosignals ◽  
2002 ◽  
Vol 11 (5) ◽  
pp. 236-250 ◽  
Author(s):  
Masaoki Kawasumi ◽  
Yuichi Hashimoto ◽  
Tomohiro Chiba ◽  
Kohsuke Kanekura ◽  
Yohichi Yamagishi ◽  
...  
Keyword(s):  
Cell Death ◽  
Amyloid Precursor Protein ◽  
Molecular Mechanisms ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Precursor Protein

Involvement of c-Jun N-terminal kinase in amyloid precursor protein-mediated neuronal cell death

2003 ◽  
Vol 84 (4) ◽  
pp. 864-877 ◽  
Author(s):  
Yuichi Hashimoto ◽  
Osahiko Tsuji ◽  
Takako Niikura ◽  
Yohichi Yamagishi ◽  
Miho Ishizaka ◽  
...  
Keyword(s):  
Cell Death ◽  
Amyloid Precursor Protein ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Precursor Protein

scholarly journals The Drosophila Amyloid Precursor Protein homologue mediates neuronal survival and neuro-glial interactions

2020 ◽  
Author(s):  
Irini A. Kessissoglou ◽  
Dominique Langui ◽  
Amr Hasan ◽  
Maral Maral ◽  
Suchetana Bias Dutta ◽  
...  
Keyword(s):  
Cell Death ◽  
Amyloid Precursor Protein ◽  
Transmembrane Protein ◽  
Neuronal Cell Death ◽  
Wnt Signaling Pathway ◽  
Physiological Role ◽  
Neuronal Cell ◽  
Adult Brain ◽  
Precursor Protein ◽  
Loss Of Function

AbstractThe amyloid precursor protein (APP) is a structurally and functionally conserved transmembrane protein whose physiological role in adult brain function and health is still unclear. Because mutations in APP cause familial Alzheimer’s disease, most research focuses on this aspect of APP biology. We investigated the physiological function of APP in the adult brain using the fruit fly Drosophila melanogaster, which harbors a single APP homologue called APP Like (APPL). Previous studies have provided evidence for the implication of APPL in neuronal wiring and axonal growth through the Wnt signaling pathway. However, like APP, APPL continues to be expressed in all neurons of the adult brain where its functions and their molecular and cellular underpinnings are unknown. We report that APPL loss of function results in the dysregulation of endolysosomal function, in both neurons and glia, with a notable enlargement of early endosomal compartment in neurons followed by neuronal cell death, the accumulation of dead neurons in the brain during a critical period at a young age and subsequent reduction in lifespan. These defects can be rescued by reduction in the levels of the early endosomal regulator Rab5, indicating a causal role of endosomal function for cell death. Finally, we show that the secreted extracellular domain of APPL is taken up by glia, regulates their endosomal morphology and this is necessary and sufficient for the clearance of neuronal debris in an axotomy model. We propose that the APP proteins represent a novel family of neuro-glial signaling proteins required for adult brain homeostasis.

scholarly journals The Drosophila amyloid precursor protein homologue mediates neuronal survival and neuroglial interactions

PLoS Biology ◽  
2020 ◽  
Vol 18 (12) ◽  
pp. e3000703 ◽  
Author(s):  
Irini A. Kessissoglou ◽  
Dominique Langui ◽  
Amr Hasan ◽  
Maral Maral ◽  
Suchetana B. Dutta ◽  
...  
Keyword(s):  
Cell Death ◽  
Amyloid Precursor Protein ◽  
Transmembrane Protein ◽  
Neuronal Cell Death ◽  
Wnt Signaling Pathway ◽  
Physiological Role ◽  
Neuronal Cell ◽  
Adult Brain ◽  
Precursor Protein ◽  
Loss Of Function

The amyloid precursor protein (APP) is a structurally and functionally conserved transmembrane protein whose physiological role in adult brain function and health is still unclear. Because mutations in APP cause familial Alzheimer’s disease (fAD), most research focuses on this aspect of APP biology. We investigated the physiological function of APP in the adult brain using the fruit fly Drosophila melanogaster, which harbors a single APP homologue called APP Like (APPL). Previous studies have provided evidence for the implication of APPL in neuronal wiring and axonal growth through the Wnt signaling pathway during development. However, like APP, APPL continues to be expressed in all neurons of the adult brain where its functions and their molecular and cellular underpinnings are unknown. We report that APPL loss of function (LOF) results in the dysregulation of endolysosomal function in neurons, with a notable enlargement of early endosomal compartments followed by neuronal cell death and the accumulation of dead neurons in the brain during a critical period at a young age. These defects can be rescued by reduction in the levels of the early endosomal regulator Rab5, indicating a causal role of endosomal function for cell death. Finally, we show that the secreted extracellular domain of APPL interacts with glia and regulates the size of their endosomes, the expression of the Draper engulfment receptor, and the clearance of neuronal debris in an axotomy model. We propose that APP proteins represent a novel family of neuroglial signaling factors required for adult brain homeostasis.

scholarly journals Viral proteins E1B19K and p35 protect sympathetic neurons from cell death induced by NGF deprivation.

1995 ◽  
Vol 128 (1) ◽  
pp. 201-208 ◽  
Author(s):  
I Martinou ◽  
P A Fernandez ◽  
M Missotten ◽  
E White ◽  
B Allet ◽  
...  
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Sympathetic Neurons ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Viral Proteins ◽  
Lymphoid Cells ◽  
Expression Vectors ◽  
Cervical Ganglia ◽  
Adenoviral Proteins

To study molecular mechanisms underlying neuronal cell death, we have used sympathetic neurons from superior cervical ganglia which undergo programmed cell death when deprived of nerve growth factor. These neurons have been microinjected with expression vectors containing cDNAs encoding selected proteins to test their regulatory influence over cell death. Using this procedure, we have shown previously that sympathetic neurons can be protected from NGF deprivation by the protooncogene Bcl-2. We now report that the E1B19K protein from adenovirus and the p35 protein from baculovirus also rescue neurons. Other adenoviral proteins, E1A and E1B55K, have no effect on neuronal survival. E1B55K, known to block apoptosis mediated by p53 in proliferative cells, failed to rescue sympathetic neurons suggesting that p53 is not involved in neuronal death induced by NGF deprivation. E1B19K and p35 were also coinjected with Bcl-Xs which blocks Bcl-2 function in lymphoid cells. Although Bcl-Xs blocked the ability of Bcl-2 to rescue neurons, it had no effect on survival that was dependent upon expression of E1B19K or p35.

scholarly journals Delta-secretase-cleaved Tau antagonizes TrkB neurotrophic signalings, mediating Alzheimer’s disease pathologies

2019 ◽  
Vol 116 (18) ◽  
pp. 9094-9102 ◽  
Author(s):  
Jie Xiang ◽  
Zhi-Hao Wang ◽  
Eun Hee Ahn ◽  
Xia Liu ◽  
Shan-Ping Yu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Molecular Mechanisms ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Trophic Factor ◽  
Tau Pathology ◽  
Trkb Receptors ◽  
Repeat Domain

BDNF, an essential trophic factor implicated in synaptic plasticity and neuronal survival, is reduced in Alzheimer’s disease (AD). BDNF deficiency’s association with Tau pathology in AD is well documented. However, the molecular mechanisms accounting for these events remain incompletely understood. Here we show that BDNF deprivation triggers Tau proteolytic cleavage by activating δ-secretase [i.e., asparagine endopeptidase (AEP)], and the resultant Tau N368 fragment binds TrkB receptors and blocks its neurotrophic signals, inducing neuronal cell death. Knockout of BDNF or TrkB receptors provokes δ-secretase activation via reducing T322 phosphorylation by Akt and subsequent Tau N368 cleavage, inducing AD-like pathology and cognitive dysfunction, which can be restored by expression of uncleavable Tau N255A/N368A mutant. Blocking the Tau N368–TrkB complex using Tau repeat-domain 1 peptide reverses this pathology. Thus, our findings support that BDNF reduction mediates Tau pathology via activating δ-secretase in AD.

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