Accumulation of murine amyloid-β mimics early Alzheimer’s disease

Abstract

Amyloidosis mouse models of Alzheimer's disease are generally established by transgenic approaches leading to an overexpression of mutated human genes that are known to be involved in the generation of amyloid-β in Alzheimer's families. Although these models made substantial contributions to the current knowledge about the 'amyloid hypothesis' of Alzheimer's disease, the overproduction of amyloid-β peptides mimics only inherited (familiar) Alzheimer's disease, which accounts for <1% of all patients with Alzheimer's disease. The inherited form is even regarded a 'rare' disease according to the regulations for funding of the European Union (www.erare.eu). Here, we show that mice that are double-deficient for neprilysin (encoded by Mme), one major amyloid-β-degrading enzyme, and the ABC transporter ABCC1, a major contributor to amyloid-β clearance from the brain, develop various aspects of sporadic Alzheimer's disease mimicking the clinical stage of mild cognitive impairment. Using behavioural tests, electrophysiology and morphological analyses, we compared different ABC transporter-deficient animals and found that alterations are most prominent in neprilysin × ABCC1 double-deficient mice. We show that these mice have a reduced probability to survive, show increased anxiety in new environments, and have a reduced working memory performance. Furthermore, we detected morphological changes in the hippocampus and amygdala, e.g. astrogliosis and reduced numbers of synapses, leading to defective long-term potentiation in functional measurements. Compared to human, murine amyloid-β is poorly aggregating, due to changes in three amino acids at N-terminal positions 5, 10, and 13. Interestingly, our findings account for the action of early occurring amyloid-β species/aggregates, i.e. monomers and small amyloid-β oligomers. Thus, neprilysin × ABCC1 double-deficient mice present a new model for early effects of amyloid-β-related mild cognitive impairment that allows investigations without artificial overexpression of inherited Alzheimer's disease genes.

The Case for Abandoning Therapeutic Chelation of Copper Ions in Alzheimer's Disease

“…A greater degree of H 2 O 2 production was reported for Cu 2+ and Fe 3+ in the presence of human Aβ 1−x vs. rat/mouse Aβ 1−x (Huang et al, 1999; Barnham et al, 2003a), which was concluded to be consistent with an absence of amyloid pathology in these animals. Although the latter is a common argument made in support of the metals hypothesis (Bush et al, 1994b; Atwood et al, 1998; Huang et al, 1999; Barnham et al, 2003a), aged rats can exhibit neuritic plaques (Vaughan and Peters, 1981) and a number of AD-related functional, morphological and behavioral changes are observed in wild type rats and mice if clearance of murine Aβ is impaired by the pharmacological inhibition or genetic ablation of Aβ degrading/clearing enzymes such as neprilysin (NEP) and ATP-binding cassette C1 (Iwata et al, 2000; Madani et al, 2006; Krohn et al, 2015). Since human and murine Aβ adopt rather different Cu 2+ coordination (Eury et al, 2011), this argues against a specific role for direct Cu-Aβ interaction and instead reinforces the importance of Aβ clearance.…”

Bexarotene Promotes Cholesterol Efflux and Restricts Apical-to-Basolateral Transport of Amyloid-β Peptides in an In Vitro Model of the Human Blood-Brain Barrier

“…The BBB also participates in the regulation of the brain pool of A␤ peptides in general and the re-entry of these peptides into the brain in particular [32][33][34][35][36]. The receptor for advanced glycation end-products (RAGE, expressed at the EC luminal membrane) is involved in the blood-tobrain transport of A␤ [32,34], whereas ABCB1 and probably ABCC1 restrict A␤ re-entry into the brain [25,37,38].…”

Sex Hormones Protect Against Amyloid‐β Induced Oxidative Stress in the Choroid Plexus Cell Line Z310

“…There are several possible explanations for this phenomenon. One possible explanation would be the modulation of Aβ efflux transporters, such as ABC MDR1 (p‐glycoprotein‐1) as described in Caco‐2 cells or ABCC1 , whose regulation by SHs has not yet been studied. Down‐regulation of these transporters would restrain the entrance of Aβ into cells and compromise the clearance of Aβ through the CP, although their up‐regulation would enhance the clearance of Aβ across the choroidal epithelia.…”