Biochemically-defined pools of amyloid-β in sporadic Alzheimer’s disease: correlation with amyloid PET

Abstract

We fractionated frontal cortical grey matter from human Alzheimer's disease and control subjects into four biochemically defined pools that represent four distinct compartments: soluble/cytosolic, peripheral membrane/vesicular cargo, integral lipid/membranous pools and aggregated/insoluble debris. Most of the readily extractable amyloid-β remains associated with a lipid/membranous compartment. There is an exchange of amyloid-β between the biochemical pools that was lost for the amyloid-β42 species in Alzheimer's disease, consistent with the peptide being irreversibly trapped in extracellular deposits. The quantitative amyloid-β data, combined with magnetic resonance imaging volumetric analysis of the amount of cortical grey matter in brain, allowed us to estimate the total mass of amyloid-β in Alzheimer's disease (6.5 mg) and control (1.7 mg) brains. The threshold positron emission tomography standard uptake value ratio of 1.4 equates to 5.0 μg amyloid-β/g of grey matter and the mean Alzheimer's disease dementia standard uptake value ratio level of 2.3 equates to 11.20 μg amyloid-β/g of grey matter. It takes 19 years to accumulate amyloid from the threshold positron emission tomography standard uptake value ratio to the mean value observed for Alzheimer's disease dementia. This accumulation time window combined with the difference of 4.8 mg of amyloid-β between Alzheimer's disease and control brain allows for a first approximation of amyloid-β accumulation of 28 ng/h. This equates to an estimated 2-5% of the total amyloid-β production being deposited as insoluble plaques. Understanding these rates of amyloid-β accumulation allows for a more quantitative approach in targeting the failure of amyloid-β clearance in sporadic Alzheimer's disease.

Aβ(1-42) tetramer and octamer structures reveal edge pores as a mechanism for membrane damage

“…To pursue the characterization of octameric species, we attempted to enrich our sample in this oligomer form. To this end, we maintained the concentration of DPC micelles constant and increased the concentration of Aβ(1-42) to mimic the consequences of an increase in the latter in the membrane (12 3D). This analysis resulted in a major peak eluting 1.4 mL earlier than β PFOs LOW_Aβ(1-42), as well as a small peak eluting at the same volume as the major peak detected for β PFOs LOW_Aβ(1-42).…”

“…However, by focusing exclusively on Aβ aggregation in solution, the membrane is overlooked. Indeed, a large number of studies have shown that the interaction of Aβ with the membrane results in the formation of membrane-associated oligomers, whose formation is considered to be directly responsible for compromising neuronal membrane integrity (8)(9)(10)(11)(12).…”

Functional Brain Network Connectivity Patterns Associated With Normal Cognition at Old-Age, Local β-amyloid, Tau, and APOE4

“…This difference needs to be taken into account when interpreting our findings on connectivity effects associated with β-amyloid vs. tau. However, β-amyloid effects may manifest in the long term, considering that aggregation of β-amyloid has been estimated to take about 19 years from β-amyloid positivity-threshold to mean values observed in AD dementia (Roberts et al, 2017).…”

The β‐secretase (BACE) inhibitor NB‐360 in preclinical models: From amyloid‐β reduction to downstream disease‐relevant effects

“…The initial investigation into the ability of NB‐360 to suppress the formation of Aβ plaques was done in the rather “mild” APP51/16 mouse model (Neumann et al, ). APP51/16 mice are one of the “slowest” mouse models for Aβ accumulation with a deposition rate of approximately 1.7 μg Aβ40·g −1 brain tissue·month −1 , but compared with the rate of Aβ deposition in the human AD brain (0.02 μg·g −1 tissue·month −1 ; Roberts et al, ), the rate of Aβ deposition in APP51/16 mice is around 100‐fold faster. Plaque deposition in APP51/16 mice starts at around 12 months, and the phase of plaque growth lasts until the mice are very old (>20 months; Rijal Upadhaya et al, ).…”