Aguzzi

Fakultäten » Medizinische Fakultät » Neuropathologie, Institut für » Prof. Dr. Adriano Aguzzi » Aguzzi

Completed research project

Title / Titel	Investigating the neuroimmunology of Alzheimer`s and prion diseases in a humanized mouse model
PDF	Abstract (PDF, 14 KB)
Summary / Zusammenfassung	Alzheimer’s disease (AD) and prion diseases (PrD) are neurodegenerative diseases initi-ated or directly caused by aggregated abnormally processed or folded proteins, affecting humans and as for prion diseases a large variety of animals (e.g. bovine spongiform en-cephalopathy [BSE]; sporadic or variant Creutzfeldt-Jakob disease [sCJD; vCJD]; chronic wasting disease [CWD]; scrapie in goat and sheep) (1). Whereas one-third of octogenarians succumb to AD, CJD typically affects one individual in a million each year. In addition, PrDs in animals still cause unexpected outbreaks in sheep and deer/elk flocks in Europe and the USA (1) and their potential effects on public health as well as mechanisms of horizontal transmission are still not clear. AD and PrD have many common features impinging on the metabolism of neuronal mem-brane proteins: the amyloid precursor protein APP in the case of AD, and the cellular prion protein PrPC in PrD. The key pathogenetic factors of both AD and PrD are neuronal mem-brane proteins: the amyloid precursor protein (APP) and the prion protein (PrPC). Their adducts, Aβ and PrPSc, are major constituents of the deposits littering the brain of AD and PrD patients. APP begets the A beta peptide, whereas PrPC begets the malignant prion pro-tein PrPSc (1). Both A beta and PrPSc are associated with disease, but we do not know what molecular events trigger their accumulation and what cellular and molecular mechanisms induce neurotoxicity. A great deal has been learned, however, about protein folding, misfolding, and aggregation; an entirely new class of intramembrane proteases has been identified; and unsuspected roles for the immune system in PrDs have been uncovered. The role of Aβ and PrPSc in disease was validated by the discovery that mutations of the respective genes result in autosomal-dominant AD and PrD. Besides APP, positional clon-ing of the genes causing familial AD led to the identification of the presenilins, which en-code the presumed proteolytic core of the γ–secretase. This landmark discovery im-mensely accelerated AD research, and its reverberations span from developmental biology to microbiology, basic cell biology and protease biochemistry. Two decades after Stanley Prusiner postulated that PrPSc is identical with the prion, i.e. the infectious principle, we still have a less-than-sketchy idea of the exact mechanism by which PrPC is converted into a pathogenic moiety, even though recent data point into this direction (2). PrPC is necessary for replication of the infectious agent and for pathogenesis (3). However, human genetics was less helpful in PrD than in AD: all cases of familial PrD segregate with PrPC mutations. No relevant genetic or physical interactors were identified: a report that histocompatibility loci would be linked to PrD susceptibility was not confirmed by others. Over the last decade, the immune system has surprisingly emerged as a key modulator of TSEs in laboratory animals and chronic inflammation was shown to alter pri-ons tropism in mouse models but also free ranging sheep suffering from mastitis. In AD cellular and molecular components of the immune system have been identified to provide a possible window for therapy. In addition, we found disease-associated prion protein (PrPSc, encoded by the Prnp gene) also in lymphoid organs of Creutzfeldt-Jakob patients. Despite fundamental differences in their biochemistry and genetics, the selection of recent advances in prion and AD research discussed in the following suggests that AD and PrD converge in many pathogenic aspects, and may even be amenable to similar therapeutic principles.
Keywords / Suchbegriffe	Alzheimer’s disease, prion diseases
Project leadership and contacts / Projektleitung und Kontakte	Prof. Dr. Adriano Aguzzi (Project Leader) adriano.aguzzi@usz.ch
Other links to external web pages	http://www.neuropathologie.usz.ch/
Funding source(s) / Unterstützt durch	Foundation
Duration of Project / Projektdauer	Jul 2003 to Jun 2011