Gene expression profile biomarkers and therapeutic targets for brain aging and age-related cognitive impairment

a gene expression profile and brain aging technology, applied in the field of gene expression profile biomarkers and therapeutic targets for brain aging, can solve the problems of limited impact, increased risk of alzheimer's disease, cognitive decline, etc., and achieve the effects of increasing neuronal vulnerability, reducing neuronal activity and/or oxidative metabolism, and increasing lipid metabolism

Inactive Publication Date: 2005-03-31
UNIV OF KENTUCKY RES FOUND
View PDF7 Cites 42 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

In one aspect of the invention, the known interactions of the identified processes suggest an integrative model of specific cellular cascades that begin in mid-life and eventually impair cognitive function and increase neuronal vulnerability. Initially decreased neuronal activity and/or oxidative metabolism trigger separate but parallel genomic cascades in neurons and glia. In neurons, the cascade results in reductions of

Problems solved by technology

Brain aging processes are enormously complex phenomena that affect multiple systems, cell types and pathways, and result in cognitive decline and increased risk of Alzheimer's disease (AD).
Thus, there is a clear need for identifying ACGs but, to date, such genes have not been discovered for any mammal.
To date, however, its impact has been limited by statistical problems, small sample sizes, and difficulty in assessing functional relevance.
Moreover, studies that have examined gene expression during brain aging using microarrays have not used sample sizes large enough to provide adequate statistical power for formal statistical testing.
The extremely large data sets generated by microarrays pose formidable bioinformatics and resource problems that have to date limited the impact of this powerful technology.
However, neither fold change analyses nor the small sample protocols widely used allow the direct estimates of variance necessary for defining type I error (false positives).
Therefore, they exhibit low detection sensitivity (hi

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Gene expression profile biomarkers and therapeutic targets for brain aging and age-related cognitive impairment
  • Gene expression profile biomarkers and therapeutic targets for brain aging and age-related cognitive impairment
  • Gene expression profile biomarkers and therapeutic targets for brain aging and age-related cognitive impairment

Examples

Experimental program
Comparison scheme
Effect test

example 1

Behavioral Results

Thirty animals in three age groups (n=10 / group) were trained sequentially on two tasks, first in the Morris spatial water maze (SWM) and then in the object memory task (OMT). Male Fischer 344 rats aged 4 months (Young, n=10), 13 months (Mid-Aged, n=10) and 24 months (Aged, n=10) were used. Overall, the training / testing lasted seven days, and hippocampal tissue was collected 24 hr later. Training or testing occurred on each day except for the 2nd and 3rd days of the seven-day sequence.

Methods used here for cognition assessment in the Morris Spatial Water Maze (SWM), a task sensitive to both hippocampal function and aging, have been described previously Norris C M & Foster T C, Neurobiol Learn Mem 71, 194-206 (1999). Briefly, rats were trained in a black tank, 1.7 M in diameter, filled with water (27±2° C.). Behavioral data were acquired with a Columbus Instruments tracking system. After habituation to the pool, animals were given cue training with a visible pla...

example 2

Gene Microarray Chip Results

Microarray analyses were performed on hippocampal CA1 tissues from each of the same behaviorally characterized 30 animals (one chip per animal), but one chip was lost for technical reasons, leaving a data set of 29 microarrays (Young=9, Mid-Aged=10, Aged=10). For tissue preparation, twenty-four hours after completion of the OMT testing, animals were anesthetized with CO2 gas and decapitated. The brains were rapidly removed and immersed in ice-cold, oxygenated artificial cerebrospinal fluid consisting of (in mM): 124 NaCl, 2 KCl, 1.25 KH2PO4, 2 MgSO4, 0.5 CaCl2, 26 NaHCO3, and 10 dextrose. Hippocampi were removed and the CA1 region from one hippocampus per animal were dissected by hand under a stereomicroscope. The CA1 tissue block from each animal was placed in a microcentrifuge tube and flash frozen in dry ice for RNA isolation.

For RNA isolation, total RNA was isolated using the TRIzol reagent and following the manufacturer's RNA isolation protocol ...

example 3

Multi-Step Gene Identification Algorithm

The analytic algorithm of the invention, which addresses the bioinformatics issues noted above, comprise three main steps aimed first, at reducing the number of comparisons (to manage type I error), second, at reliably detecting modest aging differences with global statistical analyses (by ANOVA), and third, at identifying aging-related expression changes that were quantitatively correlated with cognitive function (by Pearson's test; Armitage P & Berry G Statistical Methods in Medical Research, 2nd Edn., 200-205 (1987)) (see, FIG. 2).

Multiple Comparison Reduction Step. The expected false positives in a series of multiple comparisons (false positive rate) are predicted to be a percentage of the total statistical comparisons to be made, as defined by the p-value (i.e., tests at p<0.05 will on average generate 5% false positives). Accordingly, the absolute numbers of expected false positives can be decreased simply by reducing the total...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
Fractionaaaaaaaaaa
Electric chargeaaaaaaaaaa
Atomic weightaaaaaaaaaa
Login to view more

Abstract

A statistical and functional correlation strategy to identify changes in cellular pathways specifically linked to impaired cognitive function with aging. Analyses using the strategy identified multiple groups of genes expressed in the hippocampi of mammals, where the genes were expressed at different levels for several ages. The aging changes in expression began before mid-life. Many of the genes were involved in specific neuronal and glial pathways with previously unrecognized relationships to aging and/or cognitive decline. The processes identified by the strategy suggest a new hypothesis of brain aging in which initially decreased neuronal activity and/or oxidative metabolism trigger separate but parallel genomic cascades in neurons and glia. In neurons, the cascade results in elevations in calcium signaling and reductions of immediate early gene signaling, biosynthesis, synaptogenesis and neurite remodeling. In contrast, glia undergo increased lipid metabolism and mediate a cycle of demyelination and remyelination that induces antigen presentation, inflammation, oxidative stress and extracellular restructuring. These identified genes and the proteins they encode can be used as novel biomarkers of brain aging and as targets for developing treatment methods against age-related cognitive decline, Alzheimer's Disease and Parkinson's Disease.

Description

FIELD OF THE INVENTION The invention relates generally to genetic algorithms, and more particularly to the identification of gene expression profile biomarkers and therapeutic targets for brain aging. BACKGROUND OF THE INVENTION Brain aging processes are enormously complex phenomena that affect multiple systems, cell types and pathways, and result in cognitive decline and increased risk of Alzheimer's disease (AD). Landfield P W et al., J Neurobiol 23: 1247-1260 (1992). Although several biological mechanisms have been putatively linked to brain aging or Alzheimer's disease, including inflammation, oxidative stress, Ca2+ dyshomeostasis (Landfield, P W & Pitler T A, Science 226: 1089-1092 (1984); Landfield P W et al., J Neurobiol 23: 1247-1260 (1992)), mitochondrial dysfunction and chronic exposure to adrenal stress hormones (Landfield P W et al., Science 214: 581-584 (1981); Porter N M & Landfield P W, Nature Neurosci 1: 3-4 (1998)), the specific mechanisms and pathways, if any, th...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): C12Q1/68C12Q1/6809C12Q1/6883G16B20/00G16B50/00
CPCC12Q1/6809C12Q1/6883G06F19/28G06F19/18C12Q2600/158G16B20/00G16B50/00
Inventor LANDFIELD, PHILIP WBLALOCK, ERIC MCHAN, KUAY-CHUFOSSEX, THOMAS
Owner UNIV OF KENTUCKY RES FOUND
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap