A Possible Role for CSF Turnover and Choroid Plexus in the Pathogenesis of Late Onset Alzheimer's Disease

Abstract

According to the amyloid theory, the appearance of amyloid-β (Aβ) deposits represents a pivotal event in late onset Alzheimer's disease (LOAD). Physiologically, Aβ42 monomers are cleaned by capillary resorption, enzymatic catabolism, and cerebrospinal fluid (CSF) transport. Factors that promote the oligomerization of Aβ42 must be specified. In vitro, these monomers spontaneously form neurotoxic oligomers whose rate increases with time suggesting that the stasis of CSF favors the oligomerization. In animals, experimental hydrocephalus generates CSF stasis followed by the appearance of amyloid deposits. In normal pressure hydrocephalus, amyloid deposits are common, especially in elderly patients, and the turnover decline has the same order of magnitude as in AD. In this disease, the effects of CSF stasis are potentiated by the decline in the ability of CSF to inhibit the formation of oligomers. CSF originates from choroid plexus (CP). In LOAD, the functions of secretion, synthesis, and transport of CP are impaired and this is related to morphological modifications. These impairments favor the decrease of CSF turnover, the diminished levels of transthyretin, a sequestering protein synthesized by CP, and the oligomerization of Aβ42. They are potentiated by a reduced enzymatic catabolism and a decreased capillary reabsorption of Aβ42, both alterations being related to age.

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

“…Clinical observations showing that the choroid plexus-CSF system is altered in Alzheimer's disease support this hypothesis [134]. An alteration of choroid plexus vascular and epithelial morphology, a decrease in choroidal synthesis and transport capacity, and a decrease in CSF secretion is observed in aging, and is exacerbated in Alzheimer's disease [132,134]. The CSF circulation plays a role in amyloid beta distribution and clearance from the brain [49].…”

Oxidation-induced Structural Changes of Ceruloplasmin Foster NGR Motif Deamidation That Promotes Integrin Binding and Signaling

“…Interestingly, it has been reported that Cp can activate microglial cells (44), although the receptor underlying this mechanism has not yet been identified: one possibility is that deamidated Cp interacts with integrins. Other potential cell targets of deamidated Cp include the specialized epithelial cells of the ependymal layer and choroid plexus, which are directly in contact with the CSF and have been reported to be altered in AD (45)(46)(47).…”

Comparative Proteomics for the Evaluation of Protein Expression and Modifications in Neurodegenerative Diseases

“…Several cell types in the CNS that express integrins on their surface can be in principle the target of deamidated-Cp, including neurons, astrocytes, and microglia cells. Anyway, one of the interesting potential targets of deamidated-Cp is the specialized epithelial cells of the ependymal layer and choroid plexus, which are directly in contact with the CSF and have been reported to be altered, for example, in AD (Krzyzanowska & Carro, 2012;Perez-Gracia, Blanco, Carmona, Carro, & Ferrer, 2009;Serot, Zmudka, & Jouanny, 2012). In conclusion, the Cp alterations observed in PD and AD patients (Olivieri et al, 2011) might reflect accelerated protein aging, as a consequence of changes in the environmental redox status of pathological CSF that foster both Cp oxidation and Asn deamidation of NGR motifs, which in turn result in the loss of ferroxidase function and in a gain in integrin-binding properties.…”