Intraneuronal β‐amyloid and its interactions with proteins and subcellular organelles

Abstract

Amyloidogenic aggregation and misfolding of proteins are linked to neurodegeneration. The mechanism of neurodegeneration in Alzheimer's disease, which gives rise to severe neuronal death and memory loss, is not yet fully understood. The amyloid hypothesis remains the most accepted theory for the pathomechanism of the disease. It was suggested that β-amyloid accumulation may play a key role in initiating the neurodegenerative processes. The recent intracellular β-amyloid (iAβ) hypothesis emphasizes the primary role of iAβ to initiate the disease by interaction with cytoplasmic proteins and cell organelles, thereby triggering apoptosis. Sophisticated methods (proteomics, protein microarray, and super resolution microscopy) have been used for studying iAβ interactions with proteins and membraneous structures. The present review summarizes the studies on the origin of iAβ and the base of its neurotoxicity: interactions with cytosolic proteins and several cell organelles such as endoplasmic reticulum, endosomes, lysosomes, ribosomes, mitochondria, and the microtubular system.

Amyloid β-peptides interfere with mitochondrial preprotein import competence by a coaggregation process

“…Our work therefore adds an important aspect concerning the deleterious consequences of coaggregation processes during the etiology of neurodegenerative diseases. Many amyloid diseases involve coaggregation of different protein species (Penke et al , 2012; Sarell et al , 2013), although the pathological mechanisms are not always entirely clear. It is conceivable that amyloidogenic β-sheet peptides interact with many different endogenous proteins, resulting in their sequestration and functional impairment (Olzscha et al , 2011).…”

Intraneuronal Aβ accumulation induces hippocampal neuron hyperexcitability through A-type K+ current inhibition mediated by activation of caspases and GSK-3

“…Extracellular Aβ can bind to several cell surface receptors including LPR, RAGE, FPRL1, NMDA, and α-7AChRs (LaFerla et al, 2007; Penke et al, 2012), and the resulting receptor-Aβ complex can be then internalized into early endosomes (LaFerla et al, 2007). Furthermore, the soluble Aβ 42 complex associated with apolipoprotein E promotes Aβ internalization (Gylys et al, 2003; Kim et al, 2009; Kuszczyk et al, 2013).…”

How to Stabilize Both the Proteins and the Membranes: Diverse Effects of sHsps in Neuroprotection

“…Certain aggregates accumulate intracellularly, such as α-synuclein in PD, superoxide dismutase (SOD) in ALS, huntingtin in HD, and hyperphosphorylated tau in AD. Prion protein in prion diseases accumulates extracellularly, while Aβ peptides are accumulated both extra-and intracellularly in AD (reviewed by Penke et al 2012 ). These different aggregation-prone proteins exhibit some common structural features, e.g.…”

“…The intracellular Aβ hypothesis emphasizes the primary role of intracellular Aβ in initiating the disease by interaction with cytoplasmic proteins and membranes of cell organelles such as mitochondria and endoplasmic reticulum (ER), thereby triggering apoptosis (Penke et al 2012 ). PolyQ proteins have also been found to interact with other cellular proteins, such as transcription factors, proteasome subunits and cytoskeletal proteins, eventually leading to the repression of transcription, impairment of the protein degradation system and alteration of the neurofi lament network (Nagai et al 1999 ;Steffan et al 2000 ;Bence et al 2001, reviewed by Fujikake et al 2008.…”

“…Since the membranes of the endosomal-lysosomal (EL) system are enriched in APP and β-and γ-secretases (Yu et al 2004 ), APP internalization by endocytosis increases Aβ generation. Although most of the Aβ formed during autophagy is normally degraded within the lysosomes, in AD it is accumulated in the EL system, resulting in increased lysosomal membrane permeability, and this stimulates the release of the lysosomal enzymes into the cytoplasm, inducing apoptotic cell death (reviewed in Nixon 2006 ;Penke et al 2012 ).…”