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Tracing Neurodegenerative Disease Transmission

Studying the transmission of Alzheimer's disease and ALS, Center for Neurodegenerative Disease Research director Virginia M.Y. Lee, PhD, published findings in 2013 demonstrating that defective tau proteins create neurofibrillary tangles (NFTs) that are incorporated into normal cells and then propagate to others.  Lee and her colleagues created synthetic tau fibrils assembled from pure proteins and injected them into mouse brains, resulting in the spreading of tau tangles amidst normal neurons. This new model demonstrated the progression of Alzheimer's pathological changes through the cell-to-cell transmission of tau.

Lee's lab also showed that structural variations in a single disease protein, alpha-synuclein, can result in quite different disease onset, symptoms, severity, and individual dysfunctions.  When alpha-synuclein fibrils clump together in the neurons of Parkinson's disease patients, they can do so in at least two distinct shapes or “strains”, leading to correspondingly different impairments.  The researchers also found that one alpha-synuclein strain can actually morph into another shape with different effects, even though both are chemically identical.  The result is that this protein, generally identified with Parkinson's, can create pathologies of other neurodegenerative diseases such as Alzheimer's.

Neuropathologist John Trojanowski, MD, PhD, director of the Penn Institute on Aging, Lee, and colleagues have been investigating another side of neurodegenerative disease transmission and progression. They recently established a staging system for ALS that defines how the disease begins from a single area in the brain to spread throughout in the nervous system to reach its ultimate fatal conclusion. Examining tissue from 76 autopsies of ALS patients, Trojanowski and collaborators mapped out a four-stage pathological process for ALS that begins in the primary motor cortex and other areas associated with breathing, movement, and swallowing, moves throughout higher areas of the brain and into the frontal cortex, finally spreading into the brain's centers of memory and language. The study further supports the mounting evidence of cell-to-cell transmission of misfolded proteins from one brain area to another, not just in ALS, but also in other neurodegenerative diseases.

By analyzing a database of patients who received a therapeutic treatment and had been inadvertently exposed to pathological proteins linked to AD, PD, and other neurodegenerative diseases, Trojanowski also found no evidence indicating the possibility that the proteins responsible for these neurodegenerative conditions can transmit disease from person to person like infectious microbes.  (The team analyzed data from an existing cohort of patients who had received human growth hormone – hGH -- from cadaveric pituitary glands via a national program, as a beneficial treatment for stunted growth, before synthetic hGH was available. Nearly 7,700 patients were treated with cadaver-derived hGH in the US between 1963 and 1985. In the mid-1980s, more than 200 patients worldwide who had received the cadaveric hGH inadvertently contaminated with prion proteins from affected donor pituitary tissue.) It's a reassuring piece of the steadily evolving picture that Penn researchers are assembling on neurodegenerative disease transmission.