Impaired burrowing is the most prominent behavioral deficit of aging htau mice

Geiszler, Philippine C.; Barron, Matthew; Pardon, Marie‐Christine

doi:10.1016/j.neuroscience.2016.05.004

Cited by 25 publications

(31 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Evidence suggests that stress contributes to the etiology of these diseases by negatively impacting the HPA axis adaptive response, altering neuronal function, inducing both genetic and epigenetic changes among other pathological changes in the brain [44]. Consistent with previous studies [23,45], we report that 6-month-old Mapt −/− mice were protected from stress, as evidenced by unchanged serum CORT levels after acute restraint stress or dexamethasone injection. In line with this, the proteomic analysis did not reveal significant changes in proteins associated with glucocorticoid signaling.…”

Section: Discussionsupporting

confidence: 91%

Hippocampal Neurogenesis Is Enhanced in Adult Tau Deficient Mice

Criado‐Marrero

Sabbagh

Jones

et al. 2020

Cells

View full text Add to dashboard Cite

Tau dysfunction is common in several neurodegenerative diseases including Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Affective symptoms have often been associated with aberrant tau pathology and are commonly comorbid in patients with tauopathies, indicating a connection between tau functioning and mechanisms of depression. The current study investigated depression-like behavior in Mapt−/− mice, which contain a targeted deletion of the gene coding for tau. We show that 6-month Mapt−/− mice are resistant to depressive behaviors, as evidenced by decreased immobility time in the forced swim and tail suspension tests, as well as increased escape behavior in a learned helplessness task. Since depression has also been linked to deficient adult neurogenesis, we measured neurogenesis in the hippocampal dentate gyrus and subventricular zone using 5-bromo-2-deoxyuridine (BrdU) labeling. We found that neurogenesis is increased in the dentate gyrus of 14-month-old Mapt−/− brains compared to wild type, providing a potential mechanism for their behavioral phenotypes. In addition to the hippocampus, an upregulation of proteins involved in neurogenesis was observed in the frontal cortex and amygdala of the Mapt−/− mice using proteomic mass spectrometry. All together, these findings suggest that tau may have a role in the depressive symptoms observed in many neurodegenerative diseases and identify tau as a potential molecular target for treating depression.

show abstract

Section: Discussionsupporting

confidence: 91%

Hippocampal Neurogenesis Is Enhanced in Adult Tau Deficient Mice

Criado‐Marrero

Sabbagh

Jones

et al. 2020

Cells

View full text Add to dashboard Cite

show abstract

“…In light of this finding and the fact that tau -/- mice may exhibit unrelated deficits resulting from overall lack of MAPT [36], further analyses only report contrasts between htau and C57 data.…”

Section: Resultsmentioning

confidence: 99%

“…htau mice show evidence of somatodendritic accumulation of hyperphosphorylated tau in the hippocampus and cortex by 3 months of age [35], with paired helical filament development and evidence of cognitive/behavioral deficits by 6–9 months [35, 36]. Sixteen age-matched C57BL/6J (C57) mice were used as the primary control groups; an additional group of 16 age-matched “tau null” (tau -/- ) mice (littermates of the htau) that expressed no endogenous mouse MAPT nor the human MAPT transgene [36] were used for initial comparisons to determine the specificity of bone effects to our target model. Equal numbers of males and females ( n = 8 per sex for each strain/genotype) were used to assess sex differences related to bone phenotype.…”

Section: Methodsmentioning

confidence: 99%

Early Evidence of Low Bone Density and Decreased Serotonergic Synthesis in the Dorsal Raphe of a Tauopathy Model of Alzheimer’s Disease

Crish

Smith

Wilson

2016

JAD

View full text Add to dashboard Cite

Reduced bone mineral density (BMD) and its clinical sequelae, osteoporosis, occur at a much greater rate in patients with Alzheimer’s disease (AD), often emerging early in the disease before significant cognitive decline is seen. Reduced BMD translates to increased bone fracture risk, decreased quality of life, and increased mortality for AD patients. However, the mechanism responsible for this observation is unclear. We hypothesize that bone loss is an additional component of an AD prodrome-changes that emerge prior to dementia and are mediated by dysfunction of the central serotonergic pathways. We characterized the skeletal phenotype of htau mice that express human forms of the microtubule-associated protein tau that become pathologically hyperphosphorylated in AD. Using radiographic densitometry, we measured BMD in female and male htau mice from 2–6 months of age–time-points prior to the presence of significant tauopathy in the hippocampal/entorhinal regions characteristic of this model. We found a significantly reduced BMD phenotype in htau mice that was most pronounced in males. Using western blotting and immunofluorescence, we showed overall reduced tryptophan hydroxylase (TPH) protein in htau brainstem and a 70% reduction in TPH-positive cells in the dorsal raphe nucleus (DRN)–a pivotal structure in the regulation of the adult skeleton. Elevations of hyperphosphorylated tau (ptau) proteins were also measured in brainstem, and co-labeled immunofluorescence studies showed presence of ptau in TPH-positive cells of the DRN as early as 4 months of age in htau mice. Together, these findings demonstrate that reduced BMD occurs earlier than overt degeneration in a tau-based AD model and that pathological changes in tau phosphorylation occur in the serotonin-producing neurons of the brainstem raphe in these mice. This illuminates a need to define a mechanistic relationship between bone loss and serotonergic deficits in early AD.

show abstract

“…Food burrowing is a species-specific behavior largely dependent on the integrity of the hippocampus (55), which is suppressed in response to systemic inflammation (56,57) and is sensitive to the progression of tau pathology in hTau mice (49). The protocol was adapted from one previously described (49). For the overnight practice of food burrowing in groups, a jar containing 50 g of food pellets broken into small pieces was added to the home cage between 17:00 and 18:00 and removed between 09:00 and 10:00 the next day.…”

Section: Food Burrowingmentioning

confidence: 99%

“…Here, we first report that increased 4R tau levels in hTau/mTau +/− mice exacerbate tau hyperphosphorylation compared to hTau mice on a full mTau knockout background (hTau/mTau −/− ). Since systemic inflammation is expected to be an early event in the pathogenesis of AD, we used 3-month-old mice, corresponding to the onset of behavioral changes in these models (48,49). We also report that increasing 4R tau availability was associated with a rapid reduction in tau phosphorylation in the hippocampus, seen 4 h after inoculation with low doses of LPS, and persisting for at least 24 h.…”

Section: Introductionmentioning

confidence: 99%

Increasing Tau 4R Tau Levels Exacerbates Hippocampal Tau Hyperphosphorylation in the hTau Model of Tauopathy but Also Tau Dephosphorylation Following Acute Systemic Inflammation

et al. 2020

Self Cite

View full text Add to dashboard Cite

but hTau/mTau +/− exhibited more severe sickness behavior at the 100 µg/kg dose and a milder behavioral and cytokine response than hTau/mTau −/− mice at the 330 µg/kg dose. All LPS doses decreased tau phosphorylation at both epitopes in hTau/mTau +/− mice, but pS202 levels were selectively reduced at the 100 µg/kg dose in hTau/mTau −/− mice. Behavioral suppression and decreased tau phosphorylation persisted at 24 h following LPS administration in hTau/mTau +/− mice.

show abstract

Impaired burrowing is the most prominent behavioral deficit of aging htau mice

Abstract: Highlightshtau mice exhibit robust deficits in food burrowing.Behavioral differences between htau and mtau−/− are age-dependent.Before 6 months of age, the htau phenotype is stronger than the mtau−/− phenotype.With aging, the htau phenotype is milder than the mtau−/− phenotype.

Cited by 25 publications

References 59 publications

Hippocampal Neurogenesis Is Enhanced in Adult Tau Deficient Mice

Hippocampal Neurogenesis Is Enhanced in Adult Tau Deficient Mice

Early Evidence of Low Bone Density and Decreased Serotonergic Synthesis in the Dorsal Raphe of a Tauopathy Model of Alzheimer’s Disease

Increasing Tau 4R Tau Levels Exacerbates Hippocampal Tau Hyperphosphorylation in the hTau Model of Tauopathy but Also Tau Dephosphorylation Following Acute Systemic Inflammation

Contact Info

Product

Resources

About