Tau Deletion Prevents Stress-Induced Dendritic Atrophy in Prefrontal Cortex: Role of Synaptic Mitochondria

Abstract

Tau protein in dendrites and synapses has been recently implicated in synaptic degeneration and neuronal malfunction. Chronic stress, a well-known inducer of neuronal/synaptic atrophy, triggers hyperphosphorylation of Tau protein and cognitive deficits. However, the cause-effect relationship between these events remains to be established. To test the involvement of Tau in stress-induced impairments of cognition, we investigated the impact of stress on cognitive behavior, neuronal structure, and the synaptic proteome in the prefrontal cortex (PFC) of Tau knock-out (Tau-KO) and wild-type (WT) mice. Whereas exposure to chronic stress resulted in atrophy of apical dendrites and spine loss in PFC neurons as well as significant impairments in working memory in WT mice, such changes were absent in Tau-KO animals. Quantitative proteomic analysis of PFC synaptosomal fractions, combined with transmission electron microscopy analysis, suggested a prominent role for mitochondria in the regulation of the effects of stress. Specifically, chronically stressed animals exhibit Tau-dependent alterations in the levels of proteins involved in mitochondrial transport and oxidative phosphorylation as well as in the synaptic localization of mitochondria in PFC. These findings provide evidence for a causal role of Tau in mediating stress-elicited neuronal atrophy and cognitive impairment and indicate that Tau may exert its effects through synaptic mitochondria.

Endolysosomal degradation of Tau and its role in glucocorticoid‐driven hippocampal malfunction

“…Clinical studies suggest that stressful life events and high GC levels are risk factors for AD (Johansson et al , ; Machado et al , ); and animal studies demonstrate that prolonged exposure to environmental stress and/or elevated GC levels trigger Tau accumulation (Lopes et al , ,c; Vyas et al , ). Based on our findings identifying the Rab35/ESCRT pathway as a critical regulator of Tau degradation, we next examined whether GC treatment altered the levels of Rab35 or ESCRT pathway proteins.…”

“…Since ubiquitylation is the major signal for cargo sorting into the ESCRT pathway, these findings provide further evidence that Rab35 stimulates the endolysosomal sorting of ubiquitylated Tau. Previous studies showed that exposure to stress or high GC levels induced Tau accumulation, dendritic atrophy, and synapse loss in animals (Pinheiro et al, 2015;Lopes et al, 2016b), and that these hippocampal deficits were Tau-dependent (Lopes et al, 2016a,b). To test whether Rab35 could protect against these GC-induced effects, we injected middle-aged rats with adeno-associated virus (AAV) to express EGFP or EGFP-Rab35 in excitatory neurons of the hippocampus under control of the CaMKIIa promoter ( Fig 6C).…”

“…Furthermore, emerging studies support a crucial role for Tau in diverse brain pathologies (for review, see Sotiropoulos et al, ) including prolonged exposure to stressful conditions, a known risk factor for AD and major depressive disorder (Vyas et al , ). In particular, recent studies demonstrate that exposure to chronic environmental stress or the major stress hormones, glucocorticoids (GC), triggers the accumulation of Tau and its synaptic missorting, precipitating dendritic atrophy and synaptic dysfunction in a Tau‐dependent manner (Pinheiro et al , ; Lopes et al , ,b; Pallas‐Bazarra et al , ; Dioli et al , ). However, the cellular mechanisms responsible for stress/GC‐induced accumulation of Tau remain unclear.…”

Kinoscope: An Open-Source Computer Program for Behavioral Pharmacologists

“…In our experience (Kokras et al, 2014, 2015, 2017), using Kinoscope's visual maps as visual aids, either in real-time scoring or in later offline auditing, greatly enhanced in an efficient and engaging way the training of new student members and the troubleshooting of poor reproducibility. Positive feedback has also been received from other departments that have used the beta version of this program, and several groups have already used the program for their research (Castelhano-Carlos et al, 2014; Papazoglou et al, 2015; Wiersielis et al, 2016; Lopes et al, 2017; Caetano et al, in press). The program will be under active development, with more behavioral templates scheduled for inclusion soon (Y-maze, Light/Dark, Tail Suspension Test).…”

Stable isotope metabolic labeling suggests differential turnover of the DPYSL protein family

“…In vivo metabolic labeling with a 15 N‐labeled diet introduces the stable nitrogen isotope 15 N into amino acids of live organisms. We have previously used in vivo 15 N metabolic labeling to identify protein expression changes in mouse models of neuropsychiatric phenotypes and investigated the effects of pharmacologically manipulating these changes . Here, we show that in addition to protein expression, 15 N metabolic labeling can simultaneously yield protein turnover data, information that cannot be gained by immunochemical methods.…”