Hrvatska znanstvena bibliografija (CROSBI)

Pregled bibliografske jedinice broj: 507789

Zbornik radova

Autori: Šimić, Goran
Naslov: Pathogenesis of Alzheimer's disease
Skup: UKF Workshop “Mechanisms of regeneration and repair in neurological disorders”
Mjesto i datum: Zagreb, Hrvatska, 17.12.2010.
Ključne riječi: Alzheimer's disease; amyloid cascade hypothesis; tau hypothesis
The principal lesions of AD pathology are senile plaques (SP) composed of 39-43 amino acid fragments of amyloid beta (Aß) peptide accumulated in the extracellular space and neurofibrillary tangles (NFT) made of hyperphosphorylated microtubule-associated protein tau (MAPT) in the neurons. The disease can be differentiated by the age of onset of clinical symptoms (early / late) and by the predominance of an inherited component (familial - FAD / sporadic - SAD). The causes of FAD are known and include mutations in the genes for the transmembrane amyloid precursor protein (APP) and presenilins 1 and 2 (PS1 and PS2), which code for subunits of APP cleaving enzyme γ-secretase. The FAD accounts for a few hundred extended families worldwide, comprising less than 0.5% of cases. The dominant view on AD pathogenesis for the last 20 years has been the amyloid cascade hypothesis (Hardy et al., Science 1992). Amyloid hypothesis is based on the aforementioned discovery that a mutation in APP gene was able to induce AD in familial cases of the disease (Goate et al., Nature 1991). This led to a (somewhat premature) conclusion that Aß is the main trigger of the disease in both FAD and SAD, and that it causes all subsequent changes, including tangle formation. The finding that mutations of the MAPT gene cause a pure tauopathy without Aß accumulation (Hutton et al., Nature 1998 ; Spillantini et al., PNAS 1998) further supported this framework of interpretation. However, neuropathological data actually never fit in amyloid hypothesis (Šimić et al. Cytoskeletal changes as an alternative view on Alzheimer's disease, Period. Biol. 1998). For example, as early as 1997, Braak and colleagues have shown that tau pathology in the entorhinal and hippocampal regions precedes Aß accumulation by 27 years (Braak et al., Neurobiol Aging 1997). The most recent data suggest that this delay may even be much longer. Namely, tau-positive material labeled by the AT8 monoclonal antibody (that shows early neurofibrillary degeneration, NFD), has been found visible in high proportion (38/42) of children and young adults in the absence of Aß accumulation (an individual with Down's syndrome was the only exception) (Braak and del Tredici, Acta Neuropathol., 2011). Since AD is traditionally viewed as a disorder associated with aging (more specifically, with old age) early tau pathology seen in children and young adults, if confirmed, could completely alter our view on AD: it might not be a disease of the aged, but as atherosclerosis, a life-long disorder (Duyckaerts C, Acta Neuropathol. 2011). Taking all of these findings into account it is not surprising that over twenty recent clinical trials of potential disease-modifying drugs based on manipulation of Aß (including active immunization) have failed (Mangialasche et al., Lancet Neurol. 2010). Moreover, in the recently abandoned semagacestat trial, some patients on the drug got worse - i.e., the drug that was designed to inhibit formation of Aß speed up cognitive decline. One plausible explanation is that the formation of Aß might be the in fact brain's protective mechanism against the disease process, whereas the progression of the pathological changes of the neuronal cytoskeleton, rather that Aß burden, is crucial in determining the severity of the dementia syndrome in AD (Bierer et al., 1996). According to this new concept, beta-amyloid production is considered only as one of the factors (although a significant one in familial cases) that promotes molecular series of events underlying AD-related neuropathological changes (Šimić et al., Neuropathol. Appl. Neurobiol., 2009).
Vrsta sudjelovanja: Poster
Vrsta prezentacije u zborniku: Sažetak
Vrsta recenzije: Nema recenziju
Projekt / tema: 108-1081870-1942
Izvorni jezik: ENG
Kategorija: Stručni
Znanstvena područja:
Temeljne medicinske znanosti,Kliničke medicinske znanosti,Psihologija
Upisao u CROSBI: (, 28. Ožu. 2011. u 12:21 sati