Researchers At Penn And CHOP Fight To Thwart The Conspirators Of Neurodegeneration

By Gautami Das, Ph.D.

Dr. Alice Chen-Plotkin presents her research at the Penn Neuroscience Public Lecture. Image Credit: Gautami Das

Dr. Alice Chen-Plotkin presents her research at the Penn Neuroscience Public Lecture. Image Credit: Gautami Das

Many of us know someone suffering from a debilitating brain disease, such as amyotropic lateral sclerosis (ALS), Alzheimer’s disease (AD) or Parkinson’s disease (PD), which mainly affect the older population. It is estimated that people aged 60 and above will number nearly 2 billion by 2050 (http://www.un.org), thereby increasing potential sufferers of these diseases and resulting in a grim future for the elderly population. In the U.S. alone, the number of AD patients aged 65 years and above may triple (to 13.8 million) by 2050 [1]. To create awareness for what lies in the future for patients and families, the students of the neuroscience graduate group (NGG) at the University of Pennsylvania (UPenn) hosted a public seminar/forum called “Degeneration in the Aging Brain” at the Smilow Center for Translational Research on the evening of March 12th 2015. Three neuroscientists from UPenn and Children’s Hospital of Philadelphia (CHOP) presented TED-style talks on AD and PD in a fully packed auditorium. Prior to the talks, short activities/demonstrations to test memory and learn more about the brain were shared with participants.

Renowned neuroscientist and UPenn Professor Virginia M.Y. Lee talked about how misfolded proteins in AD and PD, tau and alpha synuclein respectively, can corrupt healthy neighboring cells of the brain. In her groundbreaking research she showed that when synthetic alpha synuclein preformed fibrils (pff) were injected in the dorsal striatum (the area of the brain affected in PD) of normal wild type mice, PD pathology in the form of phosphorylated alpha synuclein positive Lewy body (LB) like accumulation, was observed at the injection site within 30 days. The pathology later spread to interconnected parts of the striatum – cortex and olfactory bulb, recapitulating the disease progression observed in humans. By six months post-injection the mice developed severely impaired balance and motor control, thus indicating that pathology develops first followed by dopaminergic cell death [2]. According to Prof. Lee, this is a better model than the transgenic and neurotoxin-based animal models of PD, as these do not completely recapitulate the neurodegenerative cascade observed in humans. Similar observations were made in rat and monkey independently by her two collaborators. Furthermore, her work gives hope for a possible treatment for PD when she shared that alpha synuclein monoclonal antibodies can block the entry of alpha synuclein PFFs and cell-to-cell transfer of the pathologic aggregates [3]. She has also taken a similar approach in her AD research where unilateral injection of tau PFF in the hippocampus of transgenic mice led to the formation of neurofibrillary tangles (NFT) in one month on both the sides. By six months the NFTs on the ipsilateral side propagated to diverse areas of the brain that were anatomically connected to the injection site confirming that the pffs act as seeds and convert normal tau into aggregates [4]. Prof. Lee stressed to students and researchers that cell death should not be measured as a marker for neurodegenerative diseases like AD and PD because cells live for a long time with these toxic accumulations. It takes years for neurons to die when symptoms start to appear.

Another speaker, Prof. Harry Ischiropoulos from CHOP, described why he thinks antioxidants might have therapeutic role in neurodegenerative diseases. Out of the current 347 open active clinical trials in this area, only 21 aimed to slow or prevent the disease progression, 4 of which use antioxidants.

The final talk was delivered by the young and promising clinician-scientist Dr. Alice Chen-Plotkin from Perelman School of Medicine at UPenn. She shared her success in identifying ApoA1 as a new biomarker for PD [5]. Her group screened 96 plasma proteins by multiplex immunoassay in a discovery cohort of 152 patients. Out of the 11 proteins that showed nominal correlation with PD age at onset, she pursued one with the second most hit, ApoA1 (p=0.001) because of its biological relevance – being the main component of “good” or high density lipoprotein (HDL), and its important role in reverse cholesterol transport. Lower plasma levels of ApoA1 correlated with earlier PD onset. This association was also replicated in an independent cohort of 187 PD patients (p<0.001). When analyzed in a cohort of 134 high-risk, asymptomatic subjects, lower plasma ApoA1 levels associated with greater dopamine transporter deficit (p=0.037) in the putamen (area affected in PD). Lower plasma ApoA1 also correlated with the severity of PD in both the discovery and replication cohorts [5]. ApoA1 level is known to be elevated by statins and the lipophilic form can cross the blood-brain barrier. However, since only a very few patients recruited in the discovery cohort were taking a statin, its role in lowering the risk of PD is to be determined in future studies.

The lectures were followed by a reception including refreshments and drinks, where people had the opportunity to talk to the scientists. The research on neurodegenerative diseases in CHOP and UPenn shows great promise especially with respect to PD. Future studies will hopefully reveal the efficacy of antioxidants, statins or monoclonal antibodies as potential therapy for various neurodegenerative diseases.

References:

  1. Hebert LE, Weuve J, Scherr PA, Evans DA (2013) Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology 80: 1778-1783.
  2. Luk KC, Kehm V, Carroll J, Zhang B, O’Brien P, et al. (2012) Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338: 949-953.
  3. Tran HT, Chung CH, Iba M, Zhang B, Trojanowski JQ, et al. (2014) Alpha-synuclein immunotherapy blocks uptake and templated propagation of misfolded alpha-synuclein and neurodegeneration. Cell Rep 7: 2054-2065.
  4. Iba M, Guo JL, McBride JD, Zhang B, Trojanowski JQ, et al. (2013) Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer’s-like tauopathy. J Neurosci 33: 1024-1037.
  5. Qiang JK, Wong YC, Siderowf A, Hurtig HI, Xie SX, et al. (2013) Plasma apolipoprotein A1 as a biomarker for Parkinson disease. Ann Neurol 74: 119-127.
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