Alzheimer's and prion diseases: distinct pathologies, common proteolytic denominators (original) (raw)

Prion disease and Alzheimer's disease: pathogenic overlap

Acta neurobiologiae experimentalis, 2004

Prion diseases are widely recognized for their transmissibility, and it is this feature that has been studied most extensively. In recent years, public health concerns over the transmission of animal forms of prion disease, such as bovine spongiform encephalopathy and chronic wasting disease, to humans has only augmented the notion that prion diseases are primarily infectious. Yet within the spectrum of human prion diseases, often overlooked is the fact that the overwhelming majority of cases are age-dependent sporadic, or inherited processes. Closer examination of the pathophysiological processes involved in prion disease further indicates a neurodegenerative, rather than infectious disease. Indeed, the age requirement, the numerous kindreds carrying point mutations in an amyloidogenic protein, the copper binding properties of the amyloidogenic protein, the evidence of free radical damage, the presence of polymorphisms that influence disease susceptibility, the formation of amyloid...

Prion Disease Induces Alzheimer Disease—Like Neuropathologic Changes

Journal of Neuropathology & Experimental Neurology, 2015

We examined the brains of 266 patients with prion disease (PrionD) and found that 46 patients (17%) had Alzheimer disease (AD)Ylike changes. To explore potential mechanistic links between PrionD and AD, we exposed human brain aggregates (BrnAggs) to a brain homogenate from a patient with sporadic Creutzfeldt-Jakob disease and found that neurons in human BrnAggs produced many A-amyloid (AA; AA42) inclusions, whereas uninfected control-exposed human BrnAggs did not. Western blot analysis of 20 pooled Creutzfeldt-Jakob diseaseYinfected BrnAggs verified AA42 levels higher than those in controls. We next examined the CA1 region of the hippocampus from 14 patients with PrionD and found that 5 patients had low levels of scrapie-associated prion protein (PrP Sc), many AA42 intraneuronal inclusions, low apolipoprotein E-4 (APOE-4), and no significant nerve cell loss. Seven patients had high levels of PrP Sc , low AA42, high APOE-4, and 40% nerve cell loss, suggesting that APOE-4 and PrP Sc together cause neuron loss in PrionD. There were also increased levels of hyperphosphorylated tau protein (HT) and HT-positive neuropil threads and neuron bodies in both PrionD and AD groups. The brains of 6 age-matched control patients without dementia did not contain AA42 deposits; however, there were rare HT-positive threads in 5 controls, and 2 controls had few HT-positive nerve cell bodies. We conclude that PrionD may trigger biochemical changes similar to those triggered by AD and suggest that PrionD is a disease involving PrP Sc , AA42, APOE-4, and abnormal tau.

Cellular Prion Protein and Amyloid – β Oligomers in Alzheimer's Disease – There Are Connections?

2021

Alzheimer’s disease (AD) is the most common cause of dementia worldwide. Pathological deposits of neurotoxin proteins within the brain, such as amyloid-Beta and hyperphosphorylated tau tangles, are prominent features in AD. The prion protein (PrP) is involved in neurodegeneration via its conversion from the normal cellular form PrPc, to the infection form PrP Sc. Some studies indicated that posttranslationally modified PrPc isoforms plays a fundamental role in AD pathological progression. Several studies have shown that interaction of Aβ oligomers with N-terminal residues of the PrPc protein region appears critical for neuronal toxicity. The PrPc-Aβ binding always occur in AD brains and is never detected in nondemented controls and the binding of Aβ aggregates to PrPc is restricted to the N-terminus of PrPc.

The cellular prion protein and its role in Alzheimer disease

Prion, 2009

The cellular prion protein (PrP C) is a membrane-bound glycoprotein especially abundant in the central nervous system (CNS). The scrapie prion protein (PrP Sc, also termed prions) is responsible of transmissible spongiform encephalopathies (TSE), a group of neurodegenerative diseases which affect humans and other mammal species, although the presence of PrP C is needed for the establishment and further evolution of prions. The present work compares the expression and localization of PrP C between healthy human brains and those suffering from Alzheimer disease (AD). In both situations we have observed a rostrocaudal decrease in the amount of PrP C within the CNS, both by immunoblotting and immunohistochemistry techniques. PrP C is higher expressed in our control brains than in AD cases. There was a neuronal loss and astogliosis in our AD cases. There was a tendency of a lesser expression of PrP C in AD cases than in healthy ones. And in AD cases, the intensity of the expression of the unglycosylated band is higher than the di-and monoglycosylated bands. With regards to amyloid plaques, those present in AD cases were positively labeled for PrP C , a result which is further supported by the presence of PrP C in the amyloid plaques of a transgenic line of mice mimicking AD. The work was done according to Helsinki Declaration of 1975, and approved by the Ethics Committee of the Faculty of Medicine of the University of Navarre.

Insoluble cellular prion protein and its association with prion and Alzheimer diseases

Prion, 2011

T he soluble cellular prion protein (PrP C) is best known for its association with prion disease (PrD) through its conversion to a pathogenic insoluble isoform (PrP Sc). However, its deleterious effects independent of PrP Sc have recently been observed not only in PrD but also in Alzheimer disease (AD), two diseases which mainly affect cognition. At the same time, PrP C itself seems to have broad physiologic functions including involvement in cognitive processes. The PrP C that is believed to be soluble and monomeric has so far been the only PrP conformer observed in the uninfected brain. In 2006, we identified an insoluble PrP C conformer (termed iPrP C) in uninfected human and animal brains. Remarkably, the PrP Sc-like iPrP C shares the immunoreactivity behavior and fragmentation with a newly-identified PrP Sc species in a novel human PrD termed variably protease-sensitive prionopathy. Moreover, iPrP C has been observed as the major PrP species that interacts with amyloid β (Aβ) in AD. This article highlights evidence of PrP involvement in two putatively beneficial and deleterious PrP-implicated pathways in cognition and hypothesizes first, that beneficial and deleterious effects of PrP C are attributable to the chameleon-like conformation of the protein and second, that the iPrP C conformer is associated with PrD and AD.

Cellular prion protein and Alzheimer disease: link to oligomeric amyloid-β and neuronal cell death

Prion

Soluble oligomeric amyloid-β (Aβ) has been suggested to impair synaptic and neuronal function, leading to neurodegeneration that is clinically observed as the memory and cognitive dysfunction characteristic of Alzheimer disease, while the precise mechanism(s) whereby oligomeric Aβ causes neurotoxicity remains unknown. Recently, the cellular prion protein (PrP (C) ) was reported to be an essential co-factor in mediating the neurotoxic effect of oligomeric Aβ. Our recent study showed that Prnp (-/-) mice are resistant to the neurotoxic effect of oligomeric Aβ in vivo and in vitro. Furthermore, application of an anti-PrP (C) antibody or PrP (C) peptide was able to block oligomeric Aβ-induced neurotoxicity. These findings demonstrate that PrP (C) may be involved in neuropathologic conditions other than conventional prion diseases, i.e., Creutzfeldt-Jakob disease.

Therapeutics in Alzheimer's and Prion Diseases

Biochemical Society Transactions, 2002

There is increasing recognition that numerous neurodegenerative conditions have the same underlying pathogenetic mechanism, namely a change in protein conformation, where the β-sheet content is increased. In Alzheimer's disease, amyloid deposition in the form of neuritic plaques and congophilic angiopathy is driven by the conversion of normal soluble amyloid-β peptide (sAβ) to Aβ plaques; while in the prionoses the critical event is the conversion of normal prion protein, PrPc, to the disease-associated form, PrPsc. This common theme in the pathogenesis of these disorders and the extracellular localization of the accumulating abnormal protein make them highly amenable to therapeutic approaches based on experimental manipulation of protein conformation and clearance. A number of different approaches under current development include drugs which affect the processing of the precursor proteins drugs the clearance of the amyloidogenic protein, and which inhibit or prevent the confor...