Biology subjects

Craft, S.

Publications and source records attributed to Craft, S..

3 recordsLinked to original sources

bioRxiv2020

Temporal emergence of age-associated changes in cognitive and physical function in vervets (Chlorocebus aethiops sabaeus)

Dual declines in gait speed and cognitive performance are associated with increased risk of developing dementia. Characterizing the patterns of such impairments therefore is paramount to distinguishing healthy from pathological aging. Nonhuman primates such as vervet/African green monkeys (Chlorocebus aethiops sabaeus) are important models of human neurocognitive aging, yet the trajectory of dual decline has not been characterized. We therefore 1) assessed whether cognitive and physical performance (i.e., gait speed) are lower in older aged animals; 2) explored the relationship between performance in a novel task of executive function (Wake Forest Maze Task - WFMT) and a well-established assessment of working memory (Delayed Response Task - DR Task); and 3) examined the association between baseline gait speed with executive function and working memory at one-year follow-up. We found 1) physical and cognitive declines with age; 2) strong agreement between performance in the novel WFMT and DR task; and 3) that slow gait predicted poor cognitive performance in both domains. Our results suggest that older-aged vervets exhibit a coordinated suite of traits consistent with human aging and that slow gait may be a risk factor for cognitive decline. This integrative approach provides evidence that gait speed and cognitive function differ across the lifespan in female vervet monkeys, which advances them as a model that could be used to evaluate the trajectory of dual decline over time.

animal behavior and cognition↗

bioRxiv2020

Diet, psychosocial stress, and Alzheimer's disease-related neuroanatomy in female nonhuman primates

INTRODUCTIONAssociations between diet, psychosocial stress, and neurodegenerative disease, including Alzheimers disease (AD), have been reported, but causal relationships are difficult to determine in human studies. METHODSWe used structural magnetic resonance imaging in a well-validated nonhuman primate model of AD-like neuropathology to examine the longitudinal effects of diet (Mediterranean versus Western) and social subordination stress on brain anatomy, including global volumes, cortical thicknesses and volumes, and twenty individual regions of interest (ROIs). RESULTSWestern diet resulted in greater cortical thicknesses, total brain volumes and gray matter, and diminished cerebrospinal fluid and white matter volumes. Socially stressed subordinates had smaller whole brain volumes but larger ROIs relevant to AD than dominants. DISCUSSIONThe observation of increased size of AD-related brain areas is consistent with similar reports of mid-life volume increases predicting increased AD risk later in life. While the biological mechanisms underlying the findings require future investigation, these observations suggest that Western diet and psychosocial stress instigate pathologic changes that increase risk of AD-associated neuropathologies, whereas Mediterranean diet may protect the brain. RESEARCH IN CONTEXTO_LISystematic review: The authors reviewed the literature with PubMed and Google Scholar and found a number of publications which are cited that suggest that AD pathogenesis begins well before the onset of symptoms. C_LIO_LIInterpretation: Our findings support the hypothesis that Western diet and psychosocial stress may instigate neuroinflammatory responses that increase risk of later developing AD-like neuropathologies, whereas the structural stasis in the Mediterranean diet group may represent a resilient phenotype. C_LIO_LIFuture directions: The manuscript serves as a critical first step in describing risk and resilient phenotypes during middle age in a nonhuman primate model of AD-like neuropathology. This report lays the groundwork for ongoing efforts to determine whether neuroinflammatory profiles differed across diet and stress groups. Future studies should aim to understand the temporal emergence of functional disparities associated with the changes in brain structure observed here. C_LI HIGHLIGHTSO_LIGlobal brain volumes changed in response to Western, but not Mediterranean, diet. C_LIO_LIWestern diet increased cortical thickness in multiple regions relevant to AD. C_LIO_LIMediterranean diet did not alter cortical thicknesses relevant to AD. C_LIO_LIBrain regions associated with AD risk differed between low and high stress monkeys. C_LIO_LIPsychosocial stress may modulate the effects of diet on the brain. C_LI

neuroscience↗

bioRxiv2020

Aberrant DJ-1 expression underlies L-type calcium channel hypoactivity in tuberous sclerosis complex and Alzheimer's disease

L-type voltage-dependent Ca2+ channels (L-VDCC) integrate synaptic signals to facilitate a plethora of cellular mechanisms. L-VDCC dysfunction is implicated in several neurological and psychiatric diseases. Despite their importance, signals upstream of L-VDCC activity that regulate their channel density, however, are poorly defined. In disease models with overactive mammalian target of rapamycin complex 1 (mTORC1) signaling (or mTORopathies), including tuberous sclerosis (TS) and Alzheimers disease (AD), we report a novel mechanism downstream of mTORC1 signaling that results in a deficit in dendritic L-VDCC activity. Deficits in L-VDCC activity are associated with increased expression of the mTORC1-regulated RNA-binding protein DJ-1. DJ-1 binds the mRNA coding the auxiliary Ca2+ channel subunit 2{delta}2 responsible for shuttling L-VDCC to the membrane and represses its expression. Moreover, this novel DJ-1/2{delta}2/L-VDCC pathway is disrupted in human AD and preclinical models of AD and TS. Our discovery that DJ-1 directs L-VDCC activity and L-VDCC-associated protein 2{delta}2 at the synapse suggests that DJ-1/2{delta}2/L-VDCC is a common, fundamental pathway disrupted in TS and AD that can be targeted in clinical mTORopathies. Significance StatementMany neurological disorders share symptoms, despite disparity among diseases. Treatments are prescribed based on diagnosis rather than individual symptoms. While only treating symptoms may obscure the disease, mechanism-based drug development allows the two approaches to converge. Hub proteins, those that coordinate the expression of proteins that mediate specific cellular functions, may be dysregulated across a broad range of disorders. Herein, we show that the RNA-binding protein DJ-1 controls the activity of L-type voltage-dependent calcium channels (L-VDCC), via the expression of its auxiliary subunit alpha2delta2 (2{delta}2). Importantly, we demonstrate that this novel DJ-1/2{delta}2/L-VDCC pathway is commonly disrupted among neurological disorders, namely Alzheimers disease (AD) and Tuberous Sclerosis (TS). Collectively, these data rationalize mechanism-based drug therapy to treat disease.

neuroscience↗