In vivo Differential Brain Clearance and Catabolism of Monomeric and Oligomeric Alzheimer's Aβ protein

Abstract

Amyloid β (Aβ) is the major constituent of the brain deposits found in parenchymal plaques and cerebral blood vessels of patients with Alzheimer's disease (AD). Several lines of investigation support the notion that synaptic pathology, one of the strongest correlates to cognitive impairment, is related to the progressive accumulation of neurotoxic Aβ oligomers. Since the process of oligomerization/fibrillization is concentration-dependent, it is highly reliant on the homeostatic mechanisms that regulate the steady state levels of Aβ influencing the delicate balance between rate of synthesis, dynamics of aggregation, and clearance kinetics. Emerging new data suggest that reduced Aβ clearance, particularly in the aging brain, plays a critical role in the process of amyloid formation and AD pathogenesis. Using well-defined monomeric and low molecular mass oligomeric Aβ1-40 species stereotaxically injected into the brain of C57BL/6 wild-type mice in combination with biochemical and mass spectrometric analyses in CSF, our data clearly demonstrate that Aβ physiologic removal is extremely fast and involves local proteolytic degradation leading to the generation of heterogeneous C-terminally cleaved proteolytic products, while providing clear indication of the detrimental role of oligomerization for brain Aβ efflux. Immunofluorescence confocal microscopy studies provide insight into the cellular pathways involved in the brain removal and cellular uptake of Aβ. The findings indicate that clearance from brain interstitial fluid follows local and systemic paths and that in addition to the blood-brain barrier, local enzymatic degradation and the bulk flow transport through the choroid plexus into the CSF play significant roles. Our studies highlight the diverse factors influencing brain clearance and the participation of various routes of elimination opening up new research opportunities for the understanding of altered mechanisms triggering AD pathology and for the potential design of combined therapeutic strategies.

Brain-Gut-Microbiota Axis in Alzheimer’s Disease

“…60 The physiological clearance of Aβ is very efficient. 61 In the early stages of AD low Aβ concentration activates microglia through CD14 and TLR promoting phagocytosis and amyloid clearance. 4 The process of oligomerization significantly increases amyloid retention.…”

“…4 The process of oligomerization significantly increases amyloid retention. 61 Excessive microglial stimulation and increased neuroinflammatory signaling through NF-κB, proinflammatory cytokines and reactive oxidative and nitrosative stressors lead to neuronal and glial cell death. 62 Another consequence of neuroinflammation is downregulation of triggering receptor expressed on myeloid cells 2 which further impairs phagocytosis leading to the accumulation of Aβ42.…”

Elimination of substances from the brain parenchyma: efflux via perivascular pathways and via the blood–brain barrier

“…Small changes in soluble Aβ concentrations may over time lead to large changes in the formation of Aβ aggregates [ 430 – 436 ]. While it is not known which forms of Aβ are toxic, current evidence appears to suggest that within the parenchyma the main culprits are the oligomers [ 437 – 441 ].…”

Memory-Enhancing Effects of Origanum majorana Essential Oil in an Alzheimer’s Amyloid beta1-42 Rat Model: A Molecular and Behavioral Study

“…The most frequent types of amyloidosis are related to amyloid β (Aβ) deposition, which is characteristic of neurological conditions such as aging, traumatic brain injuries, or AD [ 22 ]. Aβ peptide is an internal processing product generated through serial proteolytic cleavages of the amyloid precursor protein (APP) [ 23 , 24 ]. In humans, the soluble form of this peptide is produced and released in low amounts during normal cellular activity, and it was shown to be beneficial for normal brain synaptic activity in the absence of neurotoxicity [ 25 ].…”