Abstract
Signaling between the endoplasmic reticulum (ER) and mitochondria regulates a number of key neuronal functions, many of which are perturbed in Alzheimer's disease. Moreover, damage to ER-mitochondria signaling is seen in cell and transgenic models of Alzheimer's disease. However, as yet there is little evidence that ER-mitochondria signaling is altered in human Alzheimer's disease brains. ER-mitochondria signaling is mediated by interactions between the integral ER protein VAPB and the outer mitochondrial membrane protein PTPIP51 which act to recruit and “tether” regions of ER to the mitochondrial surface. The VAPB-PTPIP51 tethers are now known to regulate a number of ER-mitochondria signaling functions including delivery of Ca2+from ER stores to mitochondria, mitochondrial ATP production, autophagy and synaptic activity. Here we investigate the VAPB-PTPIP51 tethers in post-mortem control and Alzheimer's disease brains. Quantification of ER-mitochondria signaling proteins by immunoblotting revealed loss of VAPB and PTPIP51 in cortex but not cerebellum at end-stage Alzheimer's disease. Proximity ligation assays were used to quantify the VAPB-PTPIP51 interaction in temporal cortex pyramidal neurons and cerebellar Purkinje cell neurons in control, Braak stage III-IV (early/mid-dementia) and Braak stage VI (severe dementia) cases. Pyramidal neurons degenerate in Alzheimer's disease whereas Purkinje cells are less affected. These studies revealed that the VAPB-PTPIP51 tethers are disrupted in Braak stage III-IV pyramidal but not Purkinje cell neurons. Thus, we identify a new pathogenic event in post-mortem Alzheimer's disease brains. The implications of our findings for Alzheimer's disease mechanisms are discussed.
Highlights
Signal transduction processes enable eukaryotic cells to communicate with each other and to respond to physiological stimuli
We studied vesicle-associated membrane protein-associated protein B (VAPB) and protein tyrosine phosphatase interacting protein-51 (PTPIP51) since they function to tether endoplasmic reticulum (ER) domains with mitochondria, and a number of proteins involved in the delivery of Ca2+from ER stores to mitochondria
There are 3 subtypes of inositol 1 (IP3) receptor all of which function in delivery of Ca2+to mitochondria (Bartok et al, 2019). They display differences in expression patterns within the nervous system; IP3 receptor type-1 is highly expressed in neurons in the cortex, hippocampus and cerebellum, IP3 receptor type-2 in mainly expressed in glia, and IP3 receptor type-3 is the major isoform in brain stem and spinal cord including motor neurons but is largely absent in cortex and hippocampus (De Smedt et al, 1994;Sharp et al, 1999;Watanabe et al, 2016)
Summary
Signal transduction processes enable eukaryotic cells to communicate with each other and to respond to physiological stimuli. Communications between the endoplasmic reticulum (ER) and mitochondria represent a important component of organelle signaling since this regulates a number of fundamental cellular processes These include bioenergetics, Ca2+homeostasis, lipid metabolism, mitochondrial biogenesis and trafficking, ER stress responses, autophagy and inflammation (Csordas et al, 2018;Krols et al, 2016;Lau et al, 2018;Paillusson et al, 2016;Rieusset, 2018;Rowland and Voeltz, 2012). ER-mitochondria signaling is facilitated by close physical contacts between the two organelles such that up to 20% of the mitochondrial surface is tightly apposed to ER membranes These regions of ER are termed mitochondria-associated ER membranes (MAM) (Csordas et al, 2018;Krols et al, 2016;Lau et al, 2018;Paillusson et al, 2016;Rieusset, 2018;Rowland and Voeltz, 2012). The mechanisms by which ER membranes are recruited to the mitochondrial surface are not fully understood but it is widely accepted that the process involves
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