PP1: Does A “Prion-Like” Mechanism Contribute to the Spreading of Neuropathology in Parkinson’s Disease?
Patrik Brundin
Neuronal Survival Unit; Wallenberg Neuroscience Center; Dept of Experimental Medical Science; Lund University; Lund, Sweden
Key words: Parkinson’s disease, prion mechanism, alpha-synuclein
Neuropathological aggregates of alpha-synuclein in neuronal cytoplasm and neurites are typical features of Parkinson’s disease (PD). These Lewy neurites and Lewy bodies are prominent in substantia nigra, where dopaminergic neurons degenerate. With advancing disease they are also found in several other widespread brain areas, and it has been suggested that they appear in anterior olfactory structures and the dorsal motor nucleus of the vagal nerve even before the substantia nigra is affected.
Recent studies demonstrated that Lewy bodies and neurites appear in grafted embryonic neurons.1-3 They stain for Thioflavin S, are immunoreactive for alpha-synuclein phosphorylated at serine residue 129 and exhibit a fibrillar structure in the electron microscope.4 From 2 to 5% (frequency increases over time) of the grafted dopaminergic neurons display Lewy bodies, starting around one decade after surgery. Despite these changes, some of the PD grafted patients still exhibit signs of functional recovery beyond a decade after surgery.
We, and others, are currently exploring possible mechanisms underlying the transfer of alpha-synuclein between cells and their relevance to how neuropathology normally spreads in the PD brain.5,6 We have observed that alpha-synuclein indeed can transfer between cells in culture. The process is clearly time-dependent and once inside the new cell the imported alpha-synuclein can seed aggregation of endogenous alpha-synuclein. Furthermore, we have observed transfer of host-derived alpha-synuclein into embryonic dopamine neurons grafted into the striatum of transgenic mice expressing human alpha-synuclein. We propose that a “prion-like” disease mechanism might contribute to the pathogenesis of PD and other chronic neurodegenerative disorders.6
References
1. Li, et al. Nat Med 2008; 14:501-3.
2. Kordower, et al. Nat Med 2008; 14:504-6.
3. Kordower, et al. Mov Disord 2008; 23:2303-6.
4. Li, et al. Mov Disord 2010; [Epub ahead of print].
5. Brundin, et al. Nat Rev Neurosci 2008; 9:741-5.
6. Brundin, et al. Nat Rev Mol Cell Biol 2010; 11:301-7.
PP2: Prion Protein Interaction with Amyloid-beta Oligomers of Alzheimer’s Disease
Stephen M. Strittmatter, Haakon Nygaard, David Gimbel, Erik Gunther, Ji-Won Um, Juha Lauren, Erin Coffey and Zachary Gimbel
Yale University School of Medicine; New Haven, CT USA
Key words: prion protein, Alzheimer disease, beta amyloid
Pathology and genetics support an “Amyloid Hypothesis” for Alzheimer’s (AD). Soluble oligomers of A1 have received attention as the triggers for disease. However, the neuronal targets by which oligomeric Ab induce dysfunction have been unclear. Recently, we sought an Ab-oligomer receptor with unbiased expression cloning and identified the cellular Prion Protein (PrPC). Ab-oligomers bind with nanomolar affinity to PrPC, not PrPSc. Synaptic responsiveness in hippocampal slices from adult PrP null mice is normal, but the Ab-oligomer blockade of long-term potentiation (LTP) is absent. To test the hypothesis that PrPC is essential for the ability of brain-derived Ab to suppress cognitive function, we crossed familial AD transgenes encoding APPswe and PSen1δE9 into Prnp-/- mice. Neither APP expression nor Ab level is altered by PrPC absence in these mice. However, deletion of PrPC expression rescues 5-HT axonal degeneration, loss of cortical synaptic markers and early death in APPswe/PSen1δE9 transgenic mice. The AD transgenic mice with intact PrPC expression exhibit deficits in spatial learning and memory. Mice lacking PrPC, but containing Ab plaque derived from APPswe/PSen1δE9 transgenes, show no detectable impairment of learning and memory. Thus, deletion of PrPC expression dissociates Ab accumulation from behavioural impairment in these AD mice, with the cognitive deficits selectively requiring PrPC. In ongoing studies, we are exploring the biochemical determinants for brain Ab oligomer interaction with PrPC, and the mechanism whereby Ab/PrPC complexes alter neuronal function. Overall, this line of work suggests that PrPC plays a central role in the neurological dysfunction of Alzheimer’s disease.
P1: The Contribution of Systemic Inflammation to Neurodegeneration in Protein Misfolding Diseases
V. Hugh Perry
School of Biological Sciences; University of Southampton; Southampton, UK
Key words: protein misfolding, inflammation, microglia, Alzheimer disease
Chronic neurodegenerative diseases that involve the accumulation of misfolded proteins, such as Alzheimer’s disease, Parkinson’s disease and prion disease, proceed at variable rates in different patients. The environmental factors that might contribute to the variable rates of disease progression are poorly understood. We have been interested to learn how systemic infections, common co-morbidities in the elderly, contribute to disease progression. In a mouse model of prion disease the microglia take on an activated morphology early in disease evolution but have an anti-inflammatory phenotype characterized by the presence of TGFβ, PGE2 and CCL2. We have suggested that although the microglia are ‘primed’ by the ongoing pathology they do not appear to significantly contribute to disease progression (Perry et al. 2007). Following an intraperitoneal challenge with endotoxin the systemic inflammatory response is communicated to the brain via both neural and humoral routes that leads to switching of the microglia from an anti-inflammatory phenotype to an aggressive pro-inflammatory phenotype. This pro-inflammatory phenotype is associated with exacerbation of symptoms of sickness behaviour, acceleration of the onset of behavioural deficits and increased neuronal degeneration (Cunningham et al. 2005, 2009). We investigated how systemic inflammation impacts on individuals with Alzheimer’s disease and found that those who have raised systemic levels of TNF and suffer from acute infections have accelerated cognitive decline. It appears that the communication of systemic inflammation to the brain, a normal homeostatic mechanism in the healthy brain, which has no long-term consequences, becomes maladaptive in the diseased brain and contributes to disease progression.