Alzheimer's disease pathology spreads from neuron to neuron

A research group headed by Columbia University scientist Karen Duff reported that one of the characteristic pathologies of Alzheimer’s Disease (AD) actively spreads from neuron to neuron across synapses (Liu, Drouet et al. 2012). The report, which appears in PLoS ONE, describes the age-dependant changes in the distribution of the microtubule associated protein tau (MAPT) in an inducible transgenic mouse model expressing the P301L human mutant tau protein driven by the neuropsin promoter, which yields robust differential expression in the entorhinal cortex (EC). Duff and colleagues used an antibody (MC1) that recognizes human tau in an abnormal conformation associated with early stage neurofibrillary tangles (NFT), a hallmark neuropathological lesion associated with AD. Although tau expression was restricted to the EC, abnormal tau detected by MC1 staining spread extensively through the brain in an age dependant manner, ultimately resembling the anatomical distribution of tau pathology found in the human AD brain. Staining with another antibody (AT8) used to detect a phosphorylated form of tau commonly found in NFTs yielded similar results. The authors observed abnormal tau in neurons not expressing tau and attributed this to trans-synaptic spread of tau pathology. In an effort to rule out the possibility of "leaky expression" in cells beyond the EC, they performed laser capture microdissection to rule out human transgenic tau expression in cells distal to the EC.

AD is one of several neurodegenerative disorders characterized by the aggregation of misfolded proteins into pathological aggregates. The quintessential protein misfolding diseases are the prion diseases, such as Creutfeld-Jacob disease and Kuru. These diseases are characterized by the pathogenic propagation of abnormal protein conformation, resulting in neurodegeneration. A report in 2008 regarding the apparent transmission of Lewy-Body pathology from the brain of a Parkinson’s Disease (PD) patient to an embryonic implant (Kordower, Chu et al. 2008) resulted in a flurry of investigations concerning the transmissibility, or "prion-like" behavior of many of the proteins involved in the major neurodegenerative diseases (Goedert, Clavaguera et al. 2010). Neuron to neuron transmission of alpha-synuclein, the formation of PD-associated Lewy Body pathology and ensuing neuronal cell death has been reported (Desplats, Lee et al. 2009). Kopito, investigating the properties of the polyglutamine expansions associated with Huntington’s Disease and the spinocerebellar ataxias, reported on the "persistent infection" of cells with polyglutamine aggregates (Ren, Lauckner et al. 2009). The propagation of tau pathology following injection of brain extract from a transgenic mouse expressing a mutant (P301S) human tau into animals expressing the wild-type human tau has also been reported (Clavaguera, Bolmont et al. 2009). In these experiments, while only the transgenics expressing the mutant tau typically form NFTs, injection of a brain extract from animals expressing the mutant tau induces the formation of these lesions in the animals expressing the wild-type protein. Injection of human AD brain extract induces AD-associated Abeta deposits in animals (Morales, Duran-Aniotz et al. 2011). However, D. Carleton Gajdusek, who won the Nobel Prize for identifying the prion disease Kuru, was unable to demonstrate transmissibility of AD (Goudsmit, Morrow et al. 1980).

An interview with Dr. Duff regarding these findings by NPR may be found at this site: may found at:

http://www.npr.org/2012/02/03/146350503/study-tracks-alzheimers-progression-in-mice

A New York Academy of Sciences Symposium on disease propagation in the neurodegenerative disorders was held last year. Further information may be found at:

http://www.nyas.org/Events/Detail.aspx?cid=03d7af43-2217-43a1-b728-a85ca5fd893f

PLoS ONE Article

Trans-Synaptic Spread of Tau Pathology In Vivo

References

1. Clavaguera, F., T. Bolmont, et al. (2009). "Transmission and spreading of tauopathy in transgenic mouse brain." Nat Cell Biol 11(7): 909-913.
2. Desplats, P., H. J. Lee, et al. (2009). "Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein." Proc Natl Acad Sci U S A 106(31): 13010-13015.
3. Goedert, M., F. Clavaguera, et al. (2010). "The propagation of prion-like protein inclusions in neurodegenerative diseases." Trends Neurosci 33(7): 317-325.
4. Goudsmit, J., C. H. Morrow, et al. (1980). "Evidence for and against the transmissibility of Alzheimer disease." Neurology 30(9): 945-950.
5. Kordower, J. H., Y. Chu, et al. (2008). "Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease." Nat Med 14(5): 504-506.
6. Liu, L., V. Drouet, et al. (2012). "Trans-Synaptic Spread of Tau Pathology In Vivo." PLoS One 7(2): e31302.
7. Morales, R., C. Duran-Aniotz, et al. (2011). "De novo induction of amyloid-beta deposition in vivo." Mol Psychiatry.
8. Ren, P. H., J. E. Lauckner, et al. (2009). "Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates." Nat Cell Biol 11(2): 219-225.