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.
Highlights
The most frequent form of amyloidosis in humans is related to the deposition of amyloid-β (Aβ) in Alzheimer’s disease (AD), with cumulative biochemical, genetic, and in vivo data strongly suggesting a central role for this molecule in the pathogenesis of the disorder
Over the last decade increasing evidence indicates that one of the main mechanisms leading to brain Amyloid β (Aβ) accumulation and likely contributing to AD is a defective clearance of the protein from the brain, which affects the delicate balance between degree of Aβ production, dynamics of aggregation, and rate of brain efflux
Local enzymatic degradation, efflux through the BBB, transport to the cerebrospinal fluid, peri- and para-vascular drainage along with the more recently described glymphatic system and meningeal lymphatic vessels are among the mechanisms under current investigation and with demonstrated participation in brain Aβ removal (Deane et al, 2004, 2008, 2009; Iliff et al, 2012; Morris et al, 2014, 2016; Bakker et al, 2016)
Summary
The most frequent form of amyloidosis in humans is related to the deposition of amyloid-β (Aβ) in Alzheimer’s disease (AD), with cumulative biochemical, genetic, and in vivo data strongly suggesting a central role for this molecule in the pathogenesis of the disorder. Aβ is an internal processing product of this transmembrane APP precursor molecule (Querfurth and LaFerla, 2010; Rostagno et al, 2010) generated through proteolytic cleavage by the βand γ-secretases (Masters et al, 1985b; Kang et al, 1987; Ghiso and Frangione, 2002) It is unclear what primarily triggers and drives the progression of AD, histopathologic, genetic, biochemical, and physicochemical studies, together with information obtained from transgenic animal models, strongly support the notion that abnormal aggregation/fibrillization, and subsequent Aβ tissue accumulation are key players in the disease pathogenesis (Mattson, 2004; Walsh and Selkoe, 2007; Querfurth and LaFerla, 2010; Holtzman et al, 2011). Numerous studies have shown that these soluble oligomeric forms of Aβ—which have been identified in vivo and isolated from brain, plasma, and CSF (Kuo et al, 1996; Roher et al, 1996, 2000)—are capable of affecting synaptic function by various mechanisms (Galvan and Hart, 2016), impairing glutamatergic synaptic transmission strength and plasticity, altering synaptic structure (Whalen et al, 2005), reducing efficacy of synapses and causing synaptic loss (Walsh et al, 2002; Haass and Selkoe, 2007; Nicholls et al, 2008)
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