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 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.
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