Evidence of Wnt/β-catenin alterations in brain and bone of a tauopathy mouse model of Alzheimer's disease

Crish, Samuel D.; Ball, Hope C.; Lin, Li; Novak, Kimberly; Cooper, Lisa Noelle

doi:10.1016/j.neurobiolaging.2018.03.021

Cited by 45 publications

(36 citation statements)

References 88 publications

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“…Decreased canonical Wnt signaling has previously been suggested to play a role in AD pathogenesis in patients and has also been observed in other AD animal models (Inestrosa and Varela-Nallar 2014; Jin et al 2017; Dengler-Crish et al 2018; Huang et al 2018; Tapia-Rojas and Inestrosa 2018a, b). Our aim was to investigate these findings in the App NL-F/NL-F mouse model.…”

Section: Resultsmentioning

confidence: 67%

Aberrant Excitatory–Inhibitory Synaptic Mechanisms in Entorhinal Cortex Microcircuits During the Pathogenesis of Alzheimer’s Disease

et al. 2019

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Synaptic dysfunction is widely proposed as an initial insult leading to the neurodegeneration observed in Alzheimer’s disease (AD). We hypothesize that the initial insult originates in the lateral entorhinal cortex (LEC) due to deficits in key interneuronal functions and synaptic signaling mechanisms, in particular, Wnt (Wingless/integrated). To investigate this hypothesis, we utilized the first knock-in mouse model of AD (AppNL-F/NL-F), expressing a mutant form of human amyloid-β (Aβ) precursor protein. This model shows an age-dependent accumulation of Aβ, neuroinflammation, and neurodegeneration. Prior to the typical AD pathology, we showed a decrease in canonical Wnt signaling activity first affecting the LEC in combination with synaptic hyperexcitation and severely disrupted excitatory–inhibitory inputs onto principal cells. This synaptic imbalance was consistent with a reduction in the number of parvalbumin-containing (PV) interneurons, and a reduction in the somatic inhibitory axon terminals in the LEC compared with other cortical regions. However, targeting GABAA receptors on PV cells using allosteric modulators, diazepam, zolpidem, or a nonbenzodiazepine, L-838,417 (modulator of α2/3 subunit-containing GABAA receptors), restored the excitatory–inhibitory imbalance observed at principal cells in the LEC. These data support our hypothesis, providing a rationale for targeting the synaptic imbalance in the LEC for early stage therapeutic intervention to prevent neurodegeneration in AD.

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Section: Resultsmentioning

confidence: 67%

Aberrant Excitatory–Inhibitory Synaptic Mechanisms in Entorhinal Cortex Microcircuits During the Pathogenesis of Alzheimer’s Disease

et al. 2019

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“…In addition, low bone mineral density phenotypes are manifested in AD mouse models [178–181]. Particularly, a recent study demonstrated that Wnt/β-catenin signaling is disrupted both in brain and bone of the htau mouse model of tauopathy, which has an early low bone mineral density phenotype [179]. Therefore, osteoporosis and AD could share a key mechanism of pathogenesis [182], and Wnt activators might not only reduce cognitive impairment but also prevent bone loss in the AD patients.…”

Section: Discussionmentioning

confidence: 99%

Restoring Wnt/β-catenin signaling is a promising therapeutic strategy for Alzheimer’s disease

2019

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Alzheimer’s disease (AD) is an aging-related neurological disorder characterized by synaptic loss and dementia. Wnt/β-catenin signaling is an essential signal transduction pathway that regulates numerous cellular processes including cell survival. In brain, Wnt/β-catenin signaling is not only crucial for neuronal survival and neurogenesis, but it plays important roles in regulating synaptic plasticity and blood-brain barrier integrity and function. Moreover, activation of Wnt/β-catenin signaling inhibits amyloid-β production and tau protein hyperphosphorylation in the brain. Critically, Wnt/β-catenin signaling is greatly suppressed in AD brain via multiple pathogenic mechanisms. As such, restoring Wnt/β-catenin signaling represents a unique opportunity for the rational design of novel AD therapies.

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“…Loss-of-function mutations in the Wnt signaling pathway results in skeletal fragility and decreased bone mass (Shah et al, 2015). Preclinical studies in the htau mouse demonstrated Wnt signaling deficiencies in both the brain and bones of mice with low BMD (Dengler-Crish et al, 2018). Triggering receptor expressed on myeloid cells-2 (TREM2) is one potential activator of the canonical Wnt/β-catenin pathway that may tie together bone and brain effects.…”

Section: Dementia Alzheimer's Diseasementioning

confidence: 99%

Effects of Neurological Disorders on Bone Health

2020

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Neurological diseases, particularly in the context of aging, have serious impacts on quality of life and can negatively affect bone health. The brain-bone axis is critically important for skeletal metabolism, sensory innervation, and endocrine cross-talk between these organs. This review discusses current evidence for the cellular and molecular mechanisms by which various neurological disease categories, including autoimmune, developmental, dementia-related, movement, neuromuscular, stroke, trauma, and psychological, impart changes in bone homeostasis and mass, as well as fracture risk. Likewise, how bone may affect neurological function is discussed. Gaining a better understanding of brain-bone interactions, particularly in patients with underlying neurological disorders, may lead to development of novel therapies and discovery of shared risk factors, as well as highlight the need for broad, whole-health clinical approaches toward treatment.

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Evidence of Wnt/β-catenin alterations in brain and bone of a tauopathy mouse model of Alzheimer's disease

Cited by 45 publications

References 88 publications

Aberrant Excitatory–Inhibitory Synaptic Mechanisms in Entorhinal Cortex Microcircuits During the Pathogenesis of Alzheimer’s Disease

Aberrant Excitatory–Inhibitory Synaptic Mechanisms in Entorhinal Cortex Microcircuits During the Pathogenesis of Alzheimer’s Disease

Restoring Wnt/β-catenin signaling is a promising therapeutic strategy for Alzheimer’s disease

Effects of Neurological Disorders on Bone Health

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