TRENDS in Neurosciences Vol.25 No.12 December 2002 616 Opinion http://tins.trends.com 0166-2236/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S0166-2236(02)02263-4 Opinion Alzheimer’s and prion pathologies are two lethal neurodegenerative diseases, characterized at the immunohistochemical level by extracellular lesions corresponding to proteinaceous deposits [1–5]. Both diseases can be either sporadic or of genetic origin [2,6–9]. In familial cases of Alzheimer’s disease, mutations in the genes encoding three distinct proteins – β-amyloid precursor protein (βAPP) [10–12] and presenilins 1 and 2 [13–15] – have been shown to lead to overproduction of β-amyloid peptides. These two parent peptides, of 40 to 42 amino acids, accumulate as the disease progresses and correspond to the main component of brain senile plaques [16,17]. Prion diseases are often (but not always) characterized by brain deposition of the prion protein (PrP) [18–20]. At first sight, Alzheimer’s and prion pathologies appear entirely distinct. Unlike Alzheimer’s disease, prion diseases can also be of infectious etiology [2], explaining the characteristically different frequencies with which these diseases occur. Whereas Alzheimer’s disease is the most common age-related syndrome, with about one in four people in their eighties being affected, cases of prion diseases remain extremely rare [4]. A second criterion that clearly distinguishes the two diseases relates to the two major current hypotheses concerning their etiology and, in the case of prion diseases, mode of transmission. The ‘amyloidogenic’ hypothesis of Alzheimer’s disease states that initiation of the degenerative process is related to exacerbated production of the β-amyloid peptide [21]. This fragment is produced physiologically and its concentration is tightly controlled by biosynthesis and catabolism rates [16,22–24]. At equilibrium, the peptide is likely to remain below its threshold of solubility but mutations, certain environmental conditions or other effectors could alter this steady-state level of circulating peptide. This abnormal increase in the concentration of β-amyloid probably contributes to, at least, the initiation of the aggregation and degeneration process. In prion disease, it is thought that the pathogenic process is entirely related to transformation of the normal cellular prion protein (PrP c ) into a protease-resistant and readily aggregated isoform, called PrP sc (scrapie prion protein) that could serve as a ‘matrix’ for further biophysical transformation [1,25]. Besides the drastic differences characterizing these diseases already discussed, close examination of the molecular events associated with βAPP and PrP c proteins allows striking analogies to be identified. First, both βAPP and PrP c are complex multi-domain proteins (Fig. 1) that bear potential toxic sequences (Aβ and PrP c 106–126, respectively) [26,27]. Interestingly, Aβ and PrP c 106–126 trigger similar macroscopic deleterious apoptotic phenotypes that seem to be associated with identical molecular pathways. Second, the ‘toxic domains’ of both βAPP and PrP c undergo a series of proteolytic attacks that are triggered by identical proteolytic activities and that are similarly regulated. β-Amyloid peptide and 106–126-containing PrP c fragments: common toxic mechanisms? Several initial reports suggested that the Aβ [28–30] and PrP c 106–126 [27,31] peptides could both trigger neurotoxicity and, later, be associated with apoptotic responses [32–34]. Before considering the putative mechanisms accounting for such phenotypes, some questions could legitimately be raised about the relevance of the PrP c 106–126 peptide as a probe with which to delineate PrP-associated molecular dysfunction. Unlike Aβ, the PrP c 106–126 fragment is never detectable in any physiological or pathological situations per se. However, a recent interesting paper showed that C-terminal PrP c fragments that bear part or all the PrP c 106–126 sequence at their N-terminus have different effects on intrinsic neurotoxicity in cultured neurons, indicating that PrP c 106–126 could modulate PrP-related phenotypes even when embedded in its precursor, the PrP c protein [35]. Alzheimer’s and prion diseases:distinct pathologies, common proteolytic denominators Frédéric Checler and Bruno Vincent Alzheimer’s and prion pathologies are often seen as distinct neurodegenerative diseases, particularly because the infectious character of some prion-associated pathology makes this stand apart from classical neurodegenerative, age-related syndromes. Are there specific common denominators that could link the two diseases? It appears that βAPP (β-amyloid precursor protein) and PrP c (cellular prion protein), the ‘guilty’ proteins involved in these pathologies, undergo protein-kinase-C-regulated proteolysis by identical proteases of the disintegrin family. This cleavage occurs in an analogous way, in the middle of the ‘toxic’ Aβ and PrP c 106–126 domains of βAPP and PrP c , respectively. As these two sequences trigger similar caspase-dependent and -independent cascades, this proteolytic attack could be seen as an inactivating process aimed at clearing cells of these endogenous ‘toxins’ and, thus, preventing the associated proteinaceous accumulation usually detected in affected brains. It is our opinion that targeting these disintegrins with specific ‘activators’ could be a suitable strategy to slow dow n, or even arrest, βAPP and PrP c -related aggregation and toxicity. Frédéric Checler* Bruno Vincent IPM C du CNRS, UMR6097, 660 route des Lucioles, 06560 Valbonne, France * e-mail: checler@ ipmc.cnrs.fr