Date of Award

5-20-2016

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Yousef Al-Abed

Second Advisor

Patricio Huerta

Abstract

Cognitive impairment is a major pathological symptom affecting ~5% of the general population under 50 and 10% of those over 50 years of age. It can occur as a primary symptom in neurodegenerative diseases, or as a consequence of a broad range of conditions that include metabolic, cardiovascular, malignant diseases, as well as immune disorders. A stable connection between repetitive brain trauma and cognitive impairment has been established in recent years. It is therefore perplexing that despite the abundance of diseases associated with cognitive impairment, mechanistic insight into its pathophysiology and the available therapeutic options remain limited.

In  this  study,  we  found  upregulation  of  long  terminal  repeat  (LTR) retrotransposons  as  potential  triggers  of  brain  inflammation  leading  to  cognitive impairment and show that antiretroviral drugs can be used as a therapeutic strategy. Retrotransposons are repetitive DNA elements within the mouse genome, which are derived  from  evolutionary  ancient  retroviral  germ  line  infections.  Interestingly, retrotransposons are classified as endogenous retroviruses because of their close relation to exogenous retroviruses, such as human immunodeficiency virus.

In AIM 1, we hypothesize that brain inflammation is a major driver for cognitive impairment. A review of the literature identify several mouse models that feature brain inflammation followed by cognitive deficits and immunohistochemical hallmarks of Alzheimer’s disease, such as tau hyperphosphorylation and Amyloid β aggregation. Out of these models we select the intracerebroventricular injection of streptozotocin (ICV-STZ), which induces significant brain inflammation, and has been widely used as a model for sporadic Alzheimer’s disease. The underlying mechanism for ICV-STZ is not understood.

In AIM 2, we implement a novel behavioral paradigm, termed the clockmaze task, for the assessment of hippocampus-based spatial cognition in mice. The clockmaze task respects mouse ethology and is therefore likely to become a future reference for hippocampal phenotyping and pre-clinical drug development. In contrast, the Morris water maze task, which is often used in mice but was originally designed for rats, triggers high anxiety and physical exhaustion as confounding factors affecting spatial learning in mice.

In AIM 3, we elucidate the mechanistic link between brain inflammation and cognitive dysfunction in the ICV-STZ mouse model. In vitro and in vivo studies demonstrate the induction of LTR-retrotransposons following STZ injection. Strikingly, knockout mice lacking the mitochondrial antiviral signaling protein (MAVS), an adapter for cytosolic RNA sensing pathways, are resistant to ICV-STZ induced cognitive deficit. Moreover, treatment with indinavir, a retroviral protease inhibitor, partially rescues spatial  learning  in  ICV-STZ  injected  mice.  Thus,  our  results  suggest  that  LTR-retrotransposons are part of the causal chain between brain inflammation and cognitive impairment.

This study suggests LTR-retrotransposons as pathogenic repetitive elements of the mouse genome. Similar findings have been described in Drosophila and mouse models of frontotemporal dementia. The biological role of endogenous retroviruses has not been fully elucidated. In plants, bacteria and flies, the induction of endogenous retroviruses under stressful conditions leads to improved evolutionary fitness. As organisms that have surpassed reproductive age do not impact evolutionary fitness of a species retrotransposons might be primarily pathogenic in old age.

Our contribution to the field is the identification of an inducible mouse model for retrotransposon-driven brain pathology. Our findings strongly suggest that antiretroviral treatment targeting LTR-retrotransposons is a viable strategy for halting and reversing cognitive impairment.

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