Neuropathology of Striatal Interneurons in Transgenic Nonhuman Primate Models of Huntington's Disease 公开

Lallani, Shoeb (2017)

Permanent URL: https://etd.library.emory.edu/concern/etds/6395w786j?locale=zh
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Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by chorea, dystonia, ataxia, cognitive impairment, and psychiatric disturbances. The genetic cause of HD is an expansion of a cysteine-adenine-guanine (CAG) trinucleotide repeat in exon one of the human huntingtin (HTT) gene, which leads to a poly-glutamine (poly- Q) expansion in the huntingtin (HTT) protein. The poly-Q expansion results in production and accumulation of polyglutamine aggregates and leads to regional-specific brain atrophy in the striatum and cortex. This atrophy is due mainly to the loss of striatal projection neurons, while interneurons are relatively spared. To better understand the progressive mechanism of HD and the development of therapeutic agents against HD, an animal model that can recapitulate human conditions including neuropathology and progressive clinical manifestation is important to advance our knowledge about HD. Because of close physiological, neurological, and genetic similarities between humans and nonhuman primates (NHPs), monkeys can serve as valuable models for understanding the underlying mechanism of HD. Our lab has developed a transgenic NHP model of human HD that exhibits progressive clinical manifestation similar to human HD patients. In this project, we performed in-depth stereological analysis on wild-type (WT) and HD-NHPs to evaluate the total number and density of calretinin (CR), parvalbumin (PV), and choline acetyltransferase (ChAT)-positive striatal interneurons. Our results show striatal atrophy and tendency of interneurons to be spared, which is consistent with studies in HD patients. We also see differences in the two HD-NHPs that are reminiscent of juvenile and adult progressions of HD. This study provides further support of our HD-NHP model and its potential to serve as a preclinical animal model of HD.

Table of Contents

Abstract ................................................................................................................................ 1

Background ........................................................................................................................... 2

Huntington's disease......................................................................................................................2

Striatal Cell Loss in HD....................................................................................................................5

In Vitro Models of HD.....................................................................................................................6

Animal Models of HD .....................................................................................................................7

Preliminary Work...........................................................................................................................9

Objectives ........................................................................................................................... 11

Introduction to Stereology................................................................................................... 12

Material and Methods......................................................................................................... 14

Ethics Statement..........................................................................................................................14

Animal models.............................................................................................................................14

Tissue preparation .......................................................................................................................14

Immunohistochemistry ................................................................................................................15

Stereology ...................................................................................................................................16

Results ................................................................................................................................ 17

Stereology ...................................................................................................................................17

Calretinin (CR) .................................................................................................................................... 17

Parvalbumin (PV)................................................................................................................................ 18

Choline Acetyltransferase (ChAT) ...................................................................................................... 19

Discussion ........................................................................................................................... 21

Differences Between rHD1 and rHD7 ............................................................................................21

Comparisons with HD Patients .....................................................................................................22

Why Are These Interneurons Relatively Spared?...........................................................................23

Conclusions ......................................................................................................................... 25

Future Directions................................................................................................................. 26

Figures ................................................................................................................................ 27

Figure 1. Stereology .....................................................................................................................27

Figure 2. Pre- and Post-Commissural Regions................................................................................28

Table 1. Number of Sections and Serial Section Interval Number...................................................29

Table 2. Optical Fractionator Grid and Counting Probe Size ...........................................................30

Table 3. Interneuron Counts and Percent Difference .....................................................................31

Table 4. Striatal Volume and Percent Difference ...........................................................................32

Table 5. Interneuron Density and Percent Difference ....................................................................33

Figure 3. Stereological Counts of CR+ Neurons ..............................................................................34

Figure 4. Stereological Counts of PV+ Neurons ..............................................................................35

Figure 5. Stereological Counts of ChAT+ Neurons ..........................................................................36

Figure 6. Light Micrographs of Immunostained Striatal Interneurons.............................................37

References .......................................................................................................................... 38

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