OVERVIEW

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Brain aging is the predominant risk factor for several neurodegenerative diseases, the most common of which is Alzheimer's Disease (AD).  However, the mechanisms by which aging sets the stage for neurodegeneration are not well understood.  The Musiek lab is dedicated to identifying age-related changes in the brain which lead to AD and other diseases, and to developing therapeutic strategies to prevent these changes

 

Circadian rhythms, the 24-hour rhythms of the body, are known to decline with age.  Sleep disruption and Circadian dysfunction is also prevalent in patients with AD, and may precede symptomatic dementia.  

For more information on sleep and circadian rhythms in AD, click here:

http://www.nature.com/emm/journal/v47/n3/full/emm2014121a.html

 

Circadian rhythms are generated by a transcriptional-transcriptional feedback loop which consists of several conserved circadian clock proteins.  The master circadian clock protein BMAL1 (aka Arntl) is a bHLH transcription factor which heterodimerizes with one of two other clock protein, CLOCK or NPAS2, to form an active trancriptional complex.  This complex binds to E-box motif at thousands of sites throughout the genome and drives transcription of many genes.  BMAL1/CLOCK/NPAS2 are thus referred to as the "positive limb" of the clock.  BMAL1:CLOCK/NPAS2 drives expression of several genes which then provide negative-feedback repression of BMAL1-mediated transcription.  These include Period1-3 (Per1-3), Cryptochrome1-2 (Cry1,2), and RevErba & b (Nr1d1,2), and are referred to as the "negative limb" of the clock.  This negative feedback loop is tuned by numerous inputs to oscilate with a 24 hour period, influencing many aspects of cellular function. The core clock machinery is present in most cells in the body, and many cells can exhibit cell-autonomous clock gene oscillation even when cultured in isolation.  In mice and humans, the suprachiasmatic nucleus (SCN) serves and as the master clock of the body, synchronizing the clocks in various organs with the external light-dark cycle.  Lesioning the SCN in mice renders them behaviorally arrhythmic, depsite intact function of cellular clocks throughout the body.  Conversely, global deletion of Bmal1 in mice renders them arrhythmic, but also disrupts the function of the core clock in regulating transcription.

 

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A. Hierarchical organization of the circadian clock in mammals.  The suprachiasmatic nucleus (SCN) receives light:dark information form the retina, and in turn synchronizes the cell autonomous clocks found in most organs.  B.  Molecular organization of the core circadian clock.  Bmal1:Clock dimers regulate transcription of many genes, including the negative feedback repressor Per and Cry genes.  C.  Clock-controlled gene such as RevErb show circadian oscillation in wt mouse brain, are arrhythmic and suppressed in Bmal1 KO brain, and are arrhythmic and increased in Per1/Per2 double mutant mice.

The circadian clock machinery is expressed in neurons and glia throughout the brain, though the function of clock proteins in the non-SCN brain regions is unclear. Recently, we found that deletion of Bmal1 causes severe age-related astrogliosis, synaptic degeneration, and oxidative damage.  This brain injury was caused by loss of the positive limb of the clock in the cells of the brain, but was independent of changes in sleep or whole-animal behavioral rhythm.  For more detail, get full text of the paper here:

http://www.jci.org/articles/view/70317

 

Our group has recently shown that fragmentation of circadian rhythms can be detected in human very early in the pathogenesis of AD, years before cognitive symptoms are apparent.  Cognitively-normal people who have biomarker evidence of AD pathology (by cerebrospinal fluid measures or amyloid PET imaging) have increased fragmentation of their daily activity rhythms, suggesting circadian dysfunction.  For more detail, see the paper:

https://jamanetwork.com/journals/jamaneurology/fullarticle/2670749

Also see the Media page for several popular press articale about our paper.

At this point, the human data does not tell us if circadian dysfunction plays a causative role in AD pathogenesis, or is a consequence of very early pathology changes.  To address this, we have generated mice with different forms of tissue-specific Bmal1 deletion.  Our data showed that Bmal1 deletion throughout the body disrupted the normal rhythms of amyloid-beta in the brain, and accelerated amyloid plaque accumulation.  Our findings provide the first evidence that disrupted circadian clocks might contribute to AD pathogenesis. Read the article here:

http://jem.rupress.org/content/early/2018/01/29/jem.20172347

Read the Alzforum article on our papers here:

https://www.alzforum.org/news/research-news/faulty-brain-clocks-precede-alzheimers-may-drive-pathology

The Musiek lab is focused on understanding the basic function of clock genes in neurons and glia, and exploring how the clock machinery maintains brain homeostasis and prevents neuronal injury.  We employ mice with tissue- and cell type-specific deletion of clock genes, as well as well-characterized mouse models of Alzheimer's Disease and other neurodegenerative disease, in order to address the following key questions:

 

-What is the function of the core clock machinery in neurons, astrocytes and microglia?

-How does clock function in the brain change with aging and in age-related neurodegenerative diseases?

-How does circadian clock disruption impact the neurodegenerative process?

-What critical cellular processes are controlled by the circadian clock in the brain which might link clock dysfunction to brain injury?

-How can we target the circadian clock machinery therapeutically to mitigate neurodegeneration? 

Watch a lecture given by Erik on the role of clocks in neuroinflammation and neurodegeneration, filmed at the 2019 International Anesthesia Research Society Meeting in Montreal, CA: https://www.youtube.com/watch?v=R5nQpZNmEV0&feature=youtu.be