Mitogen-activated protein kinases (MAPKs) are important signal transducing enzymes, unique to eukaryotes, that are involved in many facets of cellular regulation. Initial research concentrated on defining the components and organization of MAPK signalling cascades, but recent studies have begun to shed light on the physiological functions of these cascades in the control of gene expression, cell proliferation and programmed cell death.

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Mammalian MAP kinase signalling cascades

2016 Alzheimer's disease facts and figures

The major cell classes of the brain differ in their developmental processes, metabolism, signaling, and function To better understand the functions and interactions of the cell types that comprise these classes, we acutely purified representative populations of neurons, astrocytes, oligodendrocyte precursor cells, newly formed oligodendrocytes, myelinating oligodendrocytes, microglia, endothelial cells, and pericytes from mouse cerebral cortex We generated a transcriptome database for these eight cell types by RNA sequencing and used a sensitive algorithm to detect alternative splicing events in each cell type Bioinformatic analyses identified thousands of new cell type-enriched genes and splicing isoforms that will provide novel markers for cell identification, tools for genetic manipulation, and insights into the biology of the brain For example, our data provide clues as to how neurons and astrocytes differ in their ability to dynamically regulate glycolytic flux and lactate generation attributable to unique splicing of PKM2, the gene encoding the glycolytic enzyme pyruvate kinase This dataset will provide a powerful new resource for understanding the development and function of the brain To ensure the widespread distribution of these datasets, we have created a user-friendly website (http://webstanfordedu/group/barres_lab/brain_rnaseqhtml) that provides a platform for analyzing and comparing transciption and alternative splicing profiles for various cell classes in the brain

https://www.jneurosci.org/content/jneuro/34/36/11929.full.pdf

An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex

This report provides information to increase understanding of the public health impact of Alzheimer's disease (AD), including incidence and prevalence, mortality rates, health expenditures and costs of care, and effect on caregivers and society in general. It also explores the roles and unique challenges of long‐distance caregivers, as well as interventions that target those challenges. An estimated 5.2 million Americans have AD. Approximately 200,000 people younger than 65 years with AD comprise the younger onset AD population; 5 million comprise the older onset AD population. Throughout the coming decades, the baby boom generation is projected to add about 10 million to the total number of people in the United States with AD. Today, someone in America develops AD every 68 seconds. By 2050, one new case of AD is expected to develop every 33 seconds, or nearly a million new cases per year, and the total estimated prevalence is expected to be 13.8 million. AD is the sixth leading cause of death in the United States and the fifth leading cause of death in Americans age 65 years or older. Between 2000 and 2010, the proportion of deaths resulting from heart disease, stroke, and prostate cancer decreased 16%, 23%, and 8%, respectively, whereas the proportion resulting from AD increased 68%. The number of deaths from AD as determined by official death certificates (83,494 in 2010) likely underrepresents the number of AD‐related deaths in the United States. A projected 450,000 older Americans with AD will die in 2013, and a large proportion will die as a result of complications of AD. In 2012, more than 15 million family members and other unpaid caregivers provided an estimated 17.5 billion hours of care to people with AD and other dementias, a contribution valued at more than $216 billion. Medicare payments for services to beneficiaries age 65 years and older with AD and other dementias are three times as great as payments for beneficiaries without these conditions, and Medicaid payments are 19 times as great. Total payments in 2013 for health care, long‐term care, and hospice services for people age 65 years and older with dementia are expected to be $203 billion (not including the contributions of unpaid caregivers). An estimated 2.3 million caregivers of people with AD and other dementias live at least 1 hour away from the care recipient. These “long‐distance caregivers” face unique challenges, including difficulty in assessing the care recipient's true health condition and needs, high rates of family disagreement regarding caregiving decisions, and high out‐of‐pocket expenses for costs related to caregiving. Out‐of‐pocket costs for long‐distance caregivers are almost twice as high as for local caregivers.

2013 Alzheimer's disease facts and figures

Mechanisms and functional implications of adult neurogenesis.

Loss of synaptic integrity in the hippocampus and prefrontal cortex (PFC) may play an integral role in age-related cognitive decline. Previously, we showed age-related increases in the dendritic marker microtubule associated protein 2 (MAP-2) and the synaptic marker synaptophysin (SYN) in mice. Similarly, apolipoprotein E (apoE), involved in lipid transport and metabolism, and glial fibrillary acidic protein (GFAP), a glia specific marker, increase with age in rodents. In this study, we assessed whether these four proteins show similar age-related changes in a nonhuman primate, the rhesus macaque. Free-floating sections from the PFC and hippocampus from adult, middle-aged, and aged rhesus macaques were immunohistochemically labeled for MAP-2, SYN, apoE, and GFAP. Protein levels were measured as area occupied by fluorescence using confocal microscopy as well as by Western blot. In the PFC and hippocampus of adult and middle-aged animals, the levels of SYN, apoE, and GFAP immunoreactivity were comparable but there was a trend towards higher MAP-2 levels in middle-aged than adult animals. There was significantly less SYN and more MAP-2, apoE, and GFAP immunoreactivity in the PFC and hippocampus of aged animals compared to adult or middle-aged animals. Thus, the age-related changes in MAP-2, apoE, and GFAP levels were similar to those previously observed in rodents. On the other hand, the age-related changes in SYN levels were not, but were similar to those previously observed in the aging human brain. Taken together, these data emphasize the value of the rhesus macaque as a pragmatic translational model for human brain aging.

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Age-related decreases in SYN levels associated with increases in MAP-2, apoE, and GFAP levels in the rhesus macaque prefrontal cortex and hippocampus

Measures of anxiety, sensorimotor function, and memory in male and female mGluR4-/- mice

ApoE2 Exaggerates PTSD-Related Behavioral, Cognitive, and Neuroendocrine Alterations

Despite critical roles of the hypothalamic arcuate neurons in controlling the growth and energy homeostasis, the gene regulatory network directing their development remains unclear. Here we report that the transcription factors Dlx1/2 and Otp coordinate the balanced generation of the two functionally related neurons in the hypothalamic arcuate nucleus, GHRH-neurons promoting the growth and AgRP-neurons controlling the feeding and energy expenditure. Dlx1/2-deficient mice show a loss-of-GHRH-neurons and an increase of AgRP-neurons, and consistently develop dwarfism and consume less energy. These results indicate that Dlx1/2 are crucial for specifying the GHRH-neuronal identity and, simultaneously, for suppressing AgRP-neuronal fate. We further show that Otp is required for the generation of AgRP-neurons and that Dlx1/2 repress the expression of Otp by directly binding the Otp gene. Together, our study demonstrates that the identity of GHRH- and AgRP-neurons is synchronously specified and segregated by the Dlx1/2-Otp gene regulatory axis.

/pdf/dlx1-2-and-otp-coordinate-the-production-of-hypothalamic-1h1j9hvh5u.pdf

Jacob Raber

Papers

Age-related decreases in SYN levels associated with increases in MAP-2, apoE, and GFAP levels in the rhesus macaque prefrontal cortex and hippocampus

Measures of anxiety, sensorimotor function, and memory in male and female mGluR4-/- mice

ApoE2 Exaggerates PTSD-Related Behavioral, Cognitive, and Neuroendocrine Alterations

Dlx1/2 and Otp coordinate the production of hypothalamic GHRH- and AgRP-neurons.

Impairments in spatial memory retention of GFAP-apoE4 female mice