Prion-like Molecular Mechanisms in Alzheimer Disease

Table. Molecular similarities among prions, Aβ seeds, and Tau seeds[2,7,10,22,23]

FIGURE 1. Schematic depiction of protein misfolding and disease

FIGURE 2. Prion protein deposition (purple) and vacuoles (spongiform change) in the neocortex of a Creutzfeldt-Jakob disease patient (bar = 50 μm)

FIGURE 3. (A) Aβ-proteopathy and (B) tauopathy in the neocortex of an Alzheimer patient

Although Alzheimer disease is not infectious by any common definition of the term, research over the past 20 years has confirmed long-standing speculation that the molecular mechanism driving neurodegeneration is fundamentally the same in Alzheimer disease and the prototypical infectious proteopathy-prion disease. This mechanism is seeded protein aggregation, essentially a crystallization-like process by which certain proteins misfold into a highly stable conformation that compels like proteins to misfold and stick to one another (FIGURE 1).

The transmissibility of prions results from the transfer of proteinaceous infectious particles-prions-from one organism to another.¹ Although considerable attention has been given to this unorthodox type of infectivity, most human prion diseases, similar to Alzheimer disease, originate with the formation of disease-specific proteinaceous agents within the affected person.^1,2

The prion paradigm of disease

The prion diseases are extraordinary in that they can be infectious, genetic, or idiopathic in origin. They are rare in humans, the most common being Creutzfeldt-Jakob disease, which afflicts approximately one to two persons per million worldwide.³ Under unusual circumstances, such as endocannibalism, exposure to contaminated biologics or consumption of tainted beef, prion disease has been transmitted to humans, but a better understanding of etiology has essentially eliminated the risk of infection.³ Infectious prion diseases are more common in nonhuman species, including scrapie in sheep and chronic wasting disease in cervids; these disorders generally are not communicable to humans, with the notable exception of the bovine spongiform encephalopathy/variant Creutzfeldt-Jakob disease zoonosis that peaked in 2000 but is now largely past.³

Most human prion diseases arise endogenously, presumably with the spontaneous misfolding and aggregation of the prion protein. Years or even decades can pass between the initiation of the disease process and the emergence of signs and symptoms. As the aberrant prion proteins accumulate in the nervous system, they form deposits that are visible under the light-microscope (FIGURE 2), along with small, stealthy assemblies called oligomers that are thought to be especially toxic to cells. Relatively late in the pathogenic process, the deterioration and demise of neurons causes brain function to decline precipitously, with death often occurring within a year of clinical onset. At autopsy, the prion-laden brain is riddled with vacuoles, giving affected regions a spongiform appearance.

Alzheimer disease

Alzheimer disease bears intriguing similarities to prion diseases; it involves a chronic, degenerative and ultimately fatal disease mechanism in which misfolded proteins accumulate in the brain.² The earliest event is the structural corruption of the Aβ protein that forms senile plaques and cerebral amyloid angiopathy, followed by the misfolding and hyperphosphorylation of Tau protein that forms neurofibrillary tangles (FIGURE 3). The proliferation of these two corrupted proteins is considered the defining feature of Alzheimer disease, and like the prion protein aberran Aβ and Tau also give rise to cytotoxic oligomers.^4,5

Another similarity is that, in both disorders, the pathogenic cascade begins in the brain many years before the first clear behavioral impairments emerge.⁴ Alzheimer can be genetic or idiopathic in origin, but it has not been shown to be infectious. Nevertheless, a compelling case can be made that the proteins that define Alzheimer as a distinct disease entity-Aβ and Tau-misfold, aggregate, and spread through the brain in a manner similar to that of prions.

The prion-like properties of misfolded Aβ and Tau

In 1998, my colleague Mathias Jucker and I began a series of experiments designed to test the hypothesis that Aβ plaques and cerebral amyloid angiopathy can be precipitated in the brains of experimental animals by a prion-like mechanism.⁶ We infused small amounts of clarified brain extract from patients who had died of Alzheimer disease into the brains of mice that were genetically modified to express the human Aβ protein. The Alzheimer brain extracts triggered the aggregation of Aβ into senile plaques and cerebral amyloid angiopathy in host mice.

We then undertook a series of experiments demonstrating that, point by point, the characteristics of Aβ seeds are identical to those of prions (TABLE). Specifically, these studies showed that Aβ seeds:

1. Are protein-only agents that induce disease in susceptible hosts

2. Spread within and to the brain

3. Exist in multiple sizes and shapes (called strains)

4. Can resist inactivation by heat and formaldehyde

Importantly, a number of research groups now have shown that Tau seeds also share these molecular features with prions (Table).^7-10

Accidental Aβ seeding in humans

From the late 1950s until the mid-1980s, certain young people with short stature were treated with intramuscular injections of growth hormone derived from pituitary glands collected from human cadavers at autopsy.^11,12 Large batches of glands were homogenized to extract the hormone, which nicely accelerated the children’s growth. Many years later, however, a subset of the treated patients developed Creutzfeldt-Jakob disease, probably because some pituitaries in the homogenized lots came from patients who had died with prion disease. (In 1985, a safer, recombinant form of growth hormone was introduced.)

Hypothesizing that the large batches also were likely to include pituitaries from persons with Alzheimer disease, in 2015 researchers in London showed that several patients who had died of Creutzfeldt-Jakob disease also had significant accumulations of cerebral Aβ plaques and amyloid angiopathy at relative young ages.¹³ Subsequently, similar lesions were demonstrated in cadaveric growth hormone recipients who died of causes other than Creutzfeldt-Jakob disease.¹⁴ Since plaques and amyloid angiopathy are rare or absent in persons of similar ages who were not treated with the human growth hormone, it is plausible that the lesions were induced by AB seeds that contaminated the hormone preparations. In addition, both Creutzfeldt-Jakob disease and AB deposition have occurred in patients who received dura mater transplants that apparently were tainted by prions and/or AB seeds, respectively.^15,16

Fully developed Alzheimer pathology-including marked AB-proteopathy and tauopathy-has not been established in any of these instances. Whether recipients of cadaveric growth hormone or dura mater transplants are at a higher risk of Alzheimer disease in the future is not known. However, the transmission of cerebral amyloid angiopathy has important clinical ramifications because vascular amyloid increases the risk for cerebral hemorrhage.^17,18

Implications of the expanded prion paradigm

Experimental and iatrogenic evidence for the seedability of AB aggregation is a reminder that surgical instruments-particularly those used in neurosurgery-should be pristine. While there is no indication that Alzheimer disease can be conveyed by blood transfusion, Creutzfeldt-Jakob has, in very rare instances, been so transmitted.¹⁹ Because advancing age is a strong risk factor for Alzheimer disease and other proteopathies, it thus may not be unreasonable to consider age limits on the donation of blood and other biologics. In addition, the role of other possible environmental and physiological risk factors needs clarification, as these might be viable therapeutic targets.²⁰

Perhaps the most important implication of the expanded prion paradigm, however, is that this fundamental molecular mechanism-seeded protein aggregation-in all likelihood drives the pathogenesis of a remarkable array of complex diseases, ranging from Alzheimer disease and Creutzfeldt-Jakob disease to frontotemporal dementia, amyotrophic lateral sclerosis, Parkinson disease, Lewy body dementia, Huntington disease, non-cerebral amyloidoses, and quite possibly many others.²¹ As a unifying molecular principle, the prion paradigm can serve as the polestar for the development of therapeutic strategies for many diseases that continue to defy effective treatment.

Dr Walker is Marie and E. R. Snelling Professor, Department of Neurology and Research Professor, Yerkes National Primate Research Center, Emory University, Atlanta, GA.

References:

1. Prusiner SB. Biology and genetics of prions causing neurodegeneration. Ann Rev Genet. 2013;47:601-623.

2. Walker LC. Prion-like mechanisms in Alzheimer disease. Handbk Clin Neurol. 2018;153:303-319.

3. Will RG, Ironside JW. Sporadic and infectious human prion diseases. Cold Spring Harb Perspect Med. 2017;7(1).

4. Jack CR, Jr, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer disease. Alzh Dement. 2018;14:535-562.

5. Jucker M, Walker LC. Propagation and spread of pathogenic protein assemblies in neurodegenerative diseases. Nat Neurosci. 2018;21:1341-1349.

6. Jucker M, Walker LC. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature. 2013;501:45-51.

7. Clavaguera F, Tolnay M, Goedert M. The prion-like behavior of assembled Tau in transgenic Mice. Cold Spring Harb Perspect Med. 2017;7(10).

8. Gibbons GS, Lee VMY, Trojanowski JQ. Mechanisms of cell-to-cell transmission of pathological Tau: a review. JAMA Neurol. 2019;76:101-108.

9. Holmes BB, Diamond MI. Cellular models for the study of prions. Cold Spring Harb Perspect Med. 2017;7(2).

10. Aoyagi A, Condello C, Stöhr J, et al. AB and tau prion-like activities decline with longevity in the Alzheimer's disease human brain. Sci Transl Med. 2019;11(490).

11. Blizzard RM. History of growth hormone therapy. Indian J Pediatr. 2012;79:87-91.

12. Rudge P, Jaunmuktane Z, Adlard P, et al. Iatrogenic CJD due to pituitary-derived growth hormone with genetically determined incubation times of up to 40 years. Brain. 2015;138(Pt 11):3386-3399.

13. Jaunmuktane Z, Mead S, Ellis M, et al. Evidence for human transmission of amyloid-beta pathology and cerebral amyloid angiopathy. Nature. 2015;525:247-250.

14. Ritchie DL, Adlard P, Peden AH, et al. Amyloid-beta accumulation in the CNS in human growth hormone recipients in the UK. Acta Neuropathol. 2017;134:221-240.

15. Frontzek K, Lutz MI, Aguzzi A, et al. Amyloid-beta pathology and cerebral amyloid angiopathy are frequent in iatrogenic Creutzfeldt-Jakob disease after dural grafting. Swiss Med Wkly. 2016;146:w14287.

16. Hamaguchi T, Taniguchi Y, Sakai K, et al. Significant association of cadaveric dura mater grafting with subpial Ab deposition and meningeal amyloid angiopathy. Acta Neuropathol. 2016;132:313-315.

17. Purro SA, Farrow MA, Linehan J, et al. Transmission of amyloid-beta protein pathology from cadaveric pituitary growth hormone. Nature. 2018;564:415-419.

18. Auriel E, Greenberg SM. The pathophysiology and clinical presentation of cerebral amyloid angiopathy. Curr Atheroscler Rep. 2012;14:343-350.

19. Brown P, Brandel JP, Sato T, et al. Iatrogenic Creutzfeldt-Jakob disease, final assessment. Emerg Infect Dis. 2012;18:901-907.

20. Walker LC, Lynn DG, Chernoff YO. A standard model of Alzheimer disease? Prion. 2018;12:261-265.

21. Prusiner SB, Ed. Prion Diseases. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 2017.

22. Mirbaha H, Chen D, Morazova OA, et al. Inert and seed-competent tau monomers suggest structural origins of aggregation. Elife. 2018;7.

23. Duyckaerts C, Sazdovitch V, Ando K, et al. Neuropathology of iatrogenic Creutzfeldt-Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Abeta pathology. Acta Neuropathol. 2018;135:201-212.