Prion-like Neurodegenerative Diseases

Alzheimer’s disease, frontotemporal dementia, and Parkinson’s disease are debilitating neurodegenerative diseases which involve the pathological aggregation of proteins. Alzheimer’s disease involves the aggregation of the amyloid beta into extracellular plaques as well as aggregations of the tau protein into intracellular neurofibrillary tangles. Frontotemporal dementia similarly involves neurofibrillary tangles. Parkinson’s disease, on the other hand, involves Lewy bodies which contain a significant amount of the protein α-synuclein. Like prion diseases, the proteins likely involved in the pathogenesis of these diseases have more than one conformation, and aggregates may be able to “seed” monomers to adopt their conformation [1]. Unlike prion diseases, these diseases are not known to be contagious. There is some in vitro evidence that the aggregates involved in these neurodegenerative diseases may be able to propagate between cells. There is also some in vivo evidence, from studies involving animal models or human studies. There is speculation that aggregates involved in these diseases may propagate between cells via release following cell death, exocytosis, synaptic release, or tunnelling nanotubules [4]. Although some mechanisms involved in the propagation of pathological aggregates in neurodegenerative diseases likely different from the mechanism involved in true prion diseases, if some neurodegenerative disease processes are analogous to those observed in prion diseases this may help researchers develop new treatments for these diseases.

Introduction to Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the progressive loss of neurons in entorhinal cortex, hippocampus, and the neocortex. Pathological intracellular neurofibrillary tangles and extracellular amyloid plaques are present in patients with AD [8]. A major component of neurofibrillary tangles is hyperphorylated tau. Tau protein normally promotes the formation of microtubules in neurons. The major constituent of amyloid plaques is β-amyloid, a protein made from cleavage of a fragment of the amyloid precursor protein [1]. Frontotemporal dementia (FTD) is a related disease, characterized by the presence of neurofibrillary tangles and a distinct clinical presentation from Alzheimer’s disease. Parkinson’s disease (PD) is characterized by the loss of neurons in the midbrain, particularly dopaminergic neurons in the substantia nigra [1]. In Parkinson’s disease, Lewy Bodies containing large amounts of the protein α-synuclein are observed in neurons as well as glia [8]. Although the symptoms of some prion diseases such as Creutzfeldt-Jakob disease resemble those of AD, FTD, and PD, there are some important differences. Unlike prion diseases, AD, FTD and PD are not transmissible between individuals. In addition, there is a longer time period between initial symptoms and death in these diseases [4].

Properties of prion-like diseases

For a disease to display “prion-like” properties, it must meet several criteria. The disease must involve aggregates made up of proteins which can have more than one protein conformation. Aggregates with proteins in pathological conformations must “seed” monomers of the protein to adopt their pathological conformation. Finally, aggregates must be able to propagate between cells in vitro and in vivo, allowing the spread of pathology throughout the individual[4]. Evidence that β-amyloid, tau and α-synuclein meet all of the above criteria is discussed below.


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Amyloid beta fibrils formed in agitated and quiescent conditions have different structural properties, detectable using electron microscopy. These structural features are conserved after seeding monomers with fragments from the original fibrils [15].

Different conformations of β-amyloid fibrils have been observed through electron microscopy in vivo [15]. Fibrils with different structural features according to 13C-NMR can be generated by incubating monomers of β-amyloid in either agitated or quiescent conditions in vitro. Not only that, seeds from these fibrils induce wild-type β-amyloid monomers to form into fibrils with the same conformation. Fibrils of the two types had different levels of toxicity in cultured rat neurons [15]. There is some in vitro evidence that β-amyloid has multiple conformations of fibrils, and that seeds of these fibrils cause monomers to adopt the same conformation.

In order for pathological β-amyloid conformations to spread in a prion-like manner, misfolded β-amyloid must be taken into cells, where it can induce misfolding of β-amyloid monomers. Extracellular aggregates of β-amyloid are taken up by cultures of SN56 cells derived from neurons of the rodent septum. These aggregates are found in Lysotracker-positive vesicles [13]. β-amyloid monomers may also be concentrated in the same types of vesicles, creating an environment conducive to the propagation of β-amyloid misfolding [7].

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(a) Amyloid plaques are visible when staining for β-amyloid in hAPP transgenic mice injected with human AD brain extracts. (b) Wild-type mice do not develop these plaques. Scale bar, 500 μm [9].

There is some evidence that β-amyloid aggregates induce monomers to misfold to form aggregates in vivo. In human β-amyloid precursor protein (APP) transgenic mice injected with brain homogenates from the neocortex of human Alzheimer’s disease patients, β-amyloid plaques develop after 5 months. The APP mice do not develop these plaques on a similar time-scale [9]. If the AD brain extracts are treated to denature proteins or β-amyloid is removed through use of antibodies, β-amyloid plaques do not form in the APP mice, consistent with the idea that β-amyloid itself, rather than other factors within the isolate, is causing the formation of plaques in the APP mice [14]. Interestingly, immunization of the APP mouse with β-amyloid before injection of the AD brain extract also prevents the formation of β-amyloid plaques [14].


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(a) Tau oligomers isolated from human AD brain extracts, but not tau paired helical filaments (PHFs), disturb long-term memory formation, including changes in object exploration time between novel and familiar objects, in wild-type mice [10].

Tau fibrils formed from wildtype tau and tau with mutations found in frontotemporal dementia (for example, P301L) have different conformations, demonstrated using infrared spectroscopy [5]. In addition, fibrils formed from WT or mutant tau can induce wild-type tau monomers to form more fibrils with the same secondary structures [5]. The finding that tau has multiple conformations which are stable after seeding in vitro provides evidence that tau misfolding could propagate in a prion-like manner.

In addition, there is evidence that tau aggregates can be taken inside cells from the extracellular fluid. Aggregates of fluorescently tagged tau placed extracellularly have been found to enter cultured C17.2 cells in vitro. Interestingly, tau monomers are not able to enter cells in this way [6].

Neurodegeneration and the formation of pathological filaments of hyperphosphorylated tau are observed in transgenic mice expressing human tau with a P301S mutation found in frontotemporal dementia. Brain extracts from these the P301S tau mice to mice expressing wild-type tau causes the formation of similar tau filaments [2]. Tau aggregates have been isolated from brain extracts of patients with AD. These isolated aggregates block long-term potentiation when injected into the hippocampus of wild-type mice, which express mouse tau [10]. In addition, the injection of isolated tau aggregates from AD patients causes the formation of filaments of hyperphosphorylated mouse tau with behavioural consequences in vivo [10].


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A30P α-synuclein fibrils have a different structure than those formed from WT α-synuclein, and more readily induce WT α-synuclein monomers to form fibrils. The resulting fibrils have the same conformation as the A30P fibrils. Scale bar, 200 μm [17].

There is evidence that α-synuclein behaves in a prion-like fashion in vitro. A form of α-synuclein with an A30P mutation more readily forms fibrils which have a different conformation than fibrils formed from wild-type α-synuclein. The fibrils formed from mutant α-synuclein release fragments which act as “seeds”, promoting the formation of fibrils by wild-type α-synuclein. Not only that, the fibrils formed from wild-type α-synuclein monomers seeded in this way have the same conformation as the fibrils formed from mutant α-synuclein [17]. It has been shown that cultured neuronal stem cells from mice will take in α-synuclein from the extra-cellular fluid, and that these cells will take up α-synuclein that was released by cells engineered to overexpress α-synuclein [3]. This cell-to-cell transmission was similarly demonstrated in cultured human dopaminergic neurons, where it was also found that the cells which received α-synuclein in this way sometimes formed Lewy-body like inclusions [3].

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α-synuclein staining shows Lewy bodies in a human PD patient’s substantia nigra post-mortem. DA neurons grafted into the substantia nigra integrate with existing cells, and also develop : α-synuclein-positive Lewy bodies. Scale bars, 40 μm [11].

There is also in vivo evidence to support the idea that α-synuclein spreads in a prion-like fashion. After human patients with Parkinson’s disease have received transplants of fetal dopaminergic neurons, Lewy bodies have been found in the grafts post-mortem. These Lewy bodies contain α-synuclein [11]. Although this provides evidence that host pathology can spread to adjacent cells, it does not conclusively show that this propagation necessarily occurs in a prion-like mechanism, because there may be environmental factors or cell-cell communication involved in the propagation of Lewy bodies. A recent study provides some support for the idea that α-synuclein itself is the agent which causes the spread of Lewy bodies and resulting cell death. α-synuclein fibrils were injected directly into the striatum of wild-type mice. These mice developed Lewy bodies and showed neurodegeneration in the substantia nigra pars compacta but not the ventral tegmental area, just as occurs in human Parkinson’s disease patients [12].


Given the fact that amyloid beta, tau and α-synuclein are much larger and more polar proteins than prion protein, how can they propagate between cells? There is not yet concrete evidence to answer this question, but some have speculated that aggregate release after cell death, exocytosis, synaptic release, or tunneling nanotubules between adjacent cells may be involved in this process [1].
Understanding how pathology in Alzheimer’s disease, frontotemporal dementia, and Parkinson’s disease spreads is important for developing future therapies for these diseases. For example, if intracellular tau pathology spreads between cells through diffusion of tau aggregates between cells, antibodies for tau which remove extracellular tau aggregates might be successful in improving the symptoms of frontotemporal dementia, or even providing a cure. A recent study has found that anti-tau antibodies are indeed been effective in reducing neurodegeneration and behavioural symptoms in mutant tau transgenic mice [16]. The question of whether neurodegenerative diseases propagate in a prion-like manner has profound implications for future clinical research.

1. Brundin, P., Melki, R. & Kopito, R. (2010). Prion-like transmission of protein aggregates in neurodegenerative diseases. Nature, 11, 301-307.
2. Clavaguera, F. et al. (2009). Transmission and spreading of tauopathy in transgenic mouse brain. Nature Cell Biology, 11, 909-914.
3. Desplats, P. et al. (2009). Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein. PNAS, 106, 13010-13015.
4. Frost, B. & Diamond, M. (2010). Prion-like mechanisms in neurodegenerative diseases. Nature, 11, 155-159.
5. Frost, B. et al. (2009). Conformational diversity of wild-type tau fibrils specified by template conformation change. J. Biol. Chem., 284, 3546-3551.
6. Frost, B. et al. (2009). Propagation of tau misfolding from the outside to the inside of a cell. J. Biol. Chem., 284, 12845-12852.
7. Hu, X. et al. (2009). Amyloid seeds formed by cellular uptake, concentration, and aggregation of the amyloid-beta peptide. PNAS, 106, 20324-20329.
8. Jellinger, K. (2008). Neuropathological aspects of Alzheimer disease, Parkinson disease, and frontotemporal dementia. Neurodegenerative Dis, 5, 118-121.
9. Kane, M. D. et al. (2000). Evidence for seeding of β-amyloid by intracerebral infusion of Alzheimer brain extracts in β-amyloid precursor protein-transgenic mice. J. Neurosci., 20, 3606-3611.
10. Lasagna-Reeves C. et al. (2012). Alzheimer brain-derived tau oligomers propagate pathology from endogenous tau. Scientific Reports, 2, 1-7.
11. Li, et al. (2008). Lewy bodies in grafted neurons in subjects with PD suggest host-to-graft disease propagation. Nat Med, 14, 501-503.
12. Luk et al. (2012). Pathological α-Synuclein Transmission Initiates Parkinson-like Neurodegeneration in Non-transgenic Mice. Science, 338, 949-953.
13. Magalhaes, A. (2005). Uptake and neuritic transport of scrapie prion protein coincident with infection of neuronal cells. J. Neurosci., 25, 5207-5216.
14. Meyer-Luehmann, M. et al. (2006). Exogenous induction of cerebral β-amyloidogenesis is governed by agent and host. Science, 313, 1781–1784.
15. Petkova, A. et al. (2005). Self-propagating, molecular-level polymorphism in Alzheimer’s beta-amyloid fibrils. Science, 307, 262-265.
16. Yanamandra, K. et al. (2013). Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron, 80, 402-414.
17. Yonetani, M. et al. (2009). Conversion of wild-type α-synuclein into mutant-type fibrils and its propagation in the presence of A30P mutant. J Biol Chem, 284, 7940-7950.

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