Figure 1.

Pathomechanisms in AD (A), FTLD linked to chromosome 17 (B), PD (C) and prion diseases (D). (A) In AD, environmental factors, genetic predisposition and mutations in βAPP and PS can affect the metabolism of Aβ. Initially, small and soluble oligomeric assemblies of Aβ42 are produced, which then cause synaptic dysfunction as well as an induction of the amyloid cascade. Note the ‘shortcut' to tau pathology and FTLD via chromosome 17-linked tau mutations. (B) The major variants of chromosome 17-linked FTLD. On the left panel, FTLD cases with tau-positive inclusions (tauopathies) are described. On the right panel, the tau-negative, ubiquitin-positive cases are shown. (C) In sporadic PD and familial PD there are common pathophysiological alterations, such as oxidative stress, mitochondrial dysfunction and protein misfolding, which ultimately result in the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta. (D) In the classical form of prion diseases, conversion of PrP^C to PrP^Sc leads to a neurodegenerative and infectious disorder. The conformational transition can occur spontaneously (sporadic), or can be induced by invading PrP^Sc (acquired) or mutations (inherited). Transgenic mouse models indicated that expression of mutant PrPs can trigger neurodegeneration in the absence of infectious prion propagation; whether such disease entities exist in animals or humans is unknown. PrP^Sc: self-propagating isoform, essential component of infectious prions; CtmPrP: a transmembrane form of PrP with the C-terminus facing the cytosol; cytoPrP: cytosolically localized PrP; PG14PrP: mutant PrP containing a nine octarepeat insertion; PrPΔHD: mutant PrP lacking the internal HD.