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Acta Universitatis Lodziensis, Folia Biologica et Oecologica

Abstract

Alzheimer’s disease (AD) is a highly complex, progressive, age-related neurodegenerative human disease entity. The genetic basis of AD is strictly connected with occurrence of mutations in Amyloid Precursor (APP) gene on chromosome 21. Molecular mechanism that leads to AD development still remains unclear. Recent data reported that it is closely correlated with Endoplasmic Reticulum (ER) stress conditions, which subsequently activate Unfolded Protein Response (UPR) signaling pathways, via the induction of protein kinase RNA-like endoplasmic reticulum kinase (PERK), as a self-protective, adaptive response to adverse stress conditions. That results in the attenuation of global protein synthesis and, on the contrary, selective translation of Activating Transcriptor Factor 4 (ATF4) and secretase β. Interestingly, under prolonged, severe ER stress UPR may switch its signal into apoptotic cell death. That ensues by ATF4-CHOP-mediated activation of a range of pro-apoptotic genes and, on the other hand, downregulation of the expression of the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) genes. Current investigations suggest that inhibitions of PERK activity may contribute to the attenuation of the deposition of toxic senile plaques in the brain tissue and, as a result, prevent degeneration of neurons and decline in cognitive abilities.

Polish Abstract

Choroba Alzheimera (ang. Alzheimer’s disease, AD) jest przewlekłą, najczęściej występującą, chorobą neurodegeneracyjną prowadzącą do nieodwracalnych zmian w strukturze, biochemii i funkcjach mózgu. Neurodegeneracja Ośrodkowego Układu Nerwowego (OUN) jest wynikiem odkładania toksycznych złogów amyloidu β (Aβ) w tkance nerwowej mózgu. Rozwój AD jest przyczyną skomplikowanych interakcji między podłożem genetycznym, a czynnikami biologicznymi, które aktywują złożone szlaki molekularne w przebiegu schorzenia. Za jedną z głównych przyczyn uważa się mutacje występujące w genie kodującym Prekursorowe białko amyloidu β (ang. Amyloid beta Precursor Protein, APP) zlokalizowane w pobliżu cięcia białka APP przez wysoce specyficzne sekretazy: α, β oraz γ. Generowanie toksycznej formy Aβ o długości 42-óch aminokwasów, odkładanego w tkance mózgowej jako płytki starcze, zachodzi poprzez drogę amyloidogenną, w której uczestniczą sekretazy β oraz γ. Na podłożu molekularnym główną przyczyną rozwoju choroby AD jest akumulacja błędnie sfałdowanych lub niesfałdowanych białek w lumen Retikulum Plazmatycznego (ang. Endoplasmic Reticulum, ER). Skutkuje to bezpośrednim wywołaniem stresu ER, który prowadzi do aktywacji kinazy PERK, a następnie fosforylacji eukariotycznego czynnika inicjacji translacji 2 (eIF2α). W rezultacie w komórce nerwowej inhibowana jest translacja większości białek oraz dochodzi do preferencyjnej translacji wyłącznie takich białek takich jak ATF4 (ang. Activating Transcriptor 4) oraz, wyniku długotrwałych warunków stresowych, CHOP (ang. CCAAT-enhancer-binding protein homologous protein). Nadekspresja białka CHOP prowadzi do wzmocnienia ekspresji genów kodujących: pro-apoptotyczne białka BH3 domain-only, GADD34 (ang. DNA damage-inducible protein, GADD34 oraz białko o aktywności oksydoreduktazy ER (ang. ER oxidoreductin 1α, ERO1α). W warunkach wysokiego stężenia białka CHOP zostaje osłabiona ekspresja genów kodujących anty-apoptotyczne białka Bcl-2. W rezultacie masa tkanki nerwowej mózgu ulega znaczącemu obniżeniu w wyniku postępującego procesu neurodegeneracji na drodze apoptotycznej śmierć komórkowej w przebiegu AD.

Keywords

Amyloid β, Endoplasmic Reticulum stress, Unfolded Protein Response, eIF2α, CHOP

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