Cell surface proteoglycan-mediated uptake and accumulation of the Alzheimer's disease peptide Aβ(1–42)

Role of Membrane Tension Sensitive Endocytosis and Rho GTPases in the Uptake of the Alzheimer’s Disease Peptide Aβ(1-42)

“…The sensitivity to reduction of membrane tension could support macropinocytosis 53 but is mainly consistent with uptake via constitutively active CLIC/GEEC. 52 Importantly, we have previously observed polarized internalization of Aβ(1-42) in CHO cells, resulting from lamellipodia, 20 which are CLIC-enriched areas. 35 Furthermore, CLICs are important regulators of the cell uptake of the brain-abundant and AD-relevant glycosphingolipid GM1, which could be a putative receptor due to its reported tight binding to Aβ peptides, 41 , 49 influencing also their aggregation 77 and toxicity.…”

“… 17 The confinement of Aβ in endolysosomal vesicles subjects the peptide to aggregation promoting conditions, including low pH 18 and the presence of lipid membranes. 19 Accordingly, we and others have shown that endocytosed Aβ is aggregating inside living cells, 14 , 20 and it has been suggested that endolysosomal compartments could serve as initial sites of Aβ seed formation. 15 , 21 Interestingly, in this regard, intraneuronal buildup of Aβ appear as one of the earliest signs of AD, typically manifesting before the formation of extracellular plaques.…”

“…We and others have also demonstrated an important role for cell surface proteoglycans. 20 , 27 − 29 In this study, we further explore Aβ uptake, focusing on clathrin-independent endocytosis (CIE) mechanisms. We also explore the regulatory role of small signaling G-proteins of the Rho GTPase family, due to their key role in regulating actin dynamics during CIE 30 and their putative function as target molecules in AD pathogenesis.…”

“…Reports range from almost exclusive use of CME, 34 to situations where the majority of the cellular endocytic volume is internalized via CIE. 35 CIE is, importantly, active in neurons, contributing to cargo uptake and fast regulation of membrane turnover at synapses 36 where Aβ peptides are also present. In addition to the implicated role in Aβ monomer uptake, 13 , 20 CIE also contributes to the neuronal internalization of the APP-processing enzyme BACE1, 37 the amyloidogenic human PrP protein, 38 as well as several types of amyloid oligomers and fibrils. 39 , 40 …”

Circadian Control of Heparan Sulfate Levels Times Phagocytosis of Amyloid Beta Aggregates

“…Aβ peptides exist in two forms (Aβ40 or Aβ42) based on the cleavage of the amyloid precursor protein (APP) by β-and γ-secretase 78 . Previous studies show differential phagocytosis of Aβ42 and Aβ40, yet the key amino acids essential to binding are present in Aβ40 (Figure 5C) (13-16, HHQK) 29,79 . However, the anionic bridge between lysine 28 and alanine 42, which is broken by HSPGs to allow the formation of Aβ42 aggregates, does not occur in Aβ40, and thus HSPGs do not affect Aβ40 aggregation 71,80 .…”