Edited by: Joana A. Palha, University of Minho, Portugal
Reviewed by: Jason B. Wu, Cedars-Sinai Medical Center, USA; Catarina Oliveira, CNC-Center for Neuroscience, Portugal
*Correspondence: Eva Carro, Neuroscience Group, Instituto de Investigacion Hospital 12 de Octubre (i+12), Avenue de Córdoba s/n, 28041 Madrid, Spain. e-mail:
This article was submitted to Frontiers in Neuropharmacology, a specialty of Frontiers in Pharmacology.
This is an open-access article distributed under the terms of the
Morphological alterations of choroid plexus in Alzheimer’s disease (AD) have been extensively investigated. These changes include epithelial atrophy, thickening of the basement membrane, and stroma fibrosis. As a result, synthesis, secretory, and transportation functions are significantly altered resulting in decreased cerebrospinal fluid (CSF) turnover. Recent studies discuss the potential impacts of these changes, including the possibility of reduced resistance to stress insults and slow clearance of toxic compounds from CSF with specific reference to the amyloid peptide. Here, we review new evidences for AD-related changes in the choroid plexus. The data suggest that the significantly altered functions of the choroid plexus contribute to the multiparametric pathogenesis of late-onset AD.
In the recent years, much attention has been directed to the roles of the choroid plexus in the central nervous system (CNS) under both normal and pathological conditions. This specialized ventricular structure has recently emerged as a key player in a variety of processes that monitor and maintain the biochemical and cellular homeostasis of the CNS.
The main role of the choroid plexus is to produce cerebrospinal fluid (CSF) and to maintain the extracellular environment of the brain by monitoring the chemical exchange between the CSF and the brain tissue. This involves the surveying of the chemical and immunological status of the extracellular fluid and the removal of toxic substances as well as important roles in the regenerative processes following traumatic events. In addition to CSF, the plexus produces various peptides which can have nourishing and neuroprotective properties.
The choroid plexus is subject to various external factors and undergoes structural and physiological changes during aging and disease states. Detrimental changes in the choroid plexus anatomy, function, and CSF turnover have been found in several neurological diseases, including Alzheimer’s disease (AD; Serot et al.,
Alzheimer’s disease is characterized by the production and accumulation of β-amyloid (Aβ) species in the form of oligomers, fibrils, and large aggregates called Aβ deposits leading to classical senile plaques in the brain, and vascular deposits (amyloid angiopathy) in brain and meningeal blood vessels (Gentile et al.,
Recently, emphasis has focused on comorbidity of AD and the deficient clearance of Aβ across the blood–brain barrier (BBB; Deane et al.,
The choroid plexus is subject to morphological and physiological changes that produce a wide range of effects. In AD the choroid plexus develops abnormalities similar to those observed with aging, although greatly enhanced. Epithelial atrophy is significantly accentuated: a decrease in cell height is observed compared to age-matched controls (Serot et al.,
The appearance of neurofibrillary tangles and extracellular senile plaque deposition, whose major constituent is Aβ, are the main hallmarks of AD (Selkoe,
Soluble Aβ, a product of the secretory pathway in amyloid precursor protein (APP) processing, is produced by the choroid plexus as observed in both rat and human post-mortem tissue (Kalaria et al.,
The deficits in mitochondrial activity, increase in oxidative stress together with above mentioned morphological changes which are observed in AD, are likely to lead not only to abnormal brain Aβ clearance at the BCSFB, but also increased or defective Aβ processing from APP, which has been described in choroid plexus (Kalaria et al.,
Mitochondrial dysfunction is one of the earliest deficits identified in AD brains (Valla et al.,
On the other hand, several studies indicate that Aβ itself can impair mitochondrial function (Canevari et al.,
Oxidative damage to proteins is a relative early phenomenon in the pathogenesis of AD. A number of oxidatively damaged proteins have been reported in the hippocampus and inferior parietal lobules of cases with mild cognitive impairment and AD-related pathology corresponding to Braak stages III, IV, and V (Butterfield et al.,
Abnormal patterns of stress protein expression are found in the cerebral cortex and hippocampus of AD subjects (Anthony et al.,
In a recent study from our group, we have described an increased nitric oxide (NO) production by the choroid plexus of AD patients, associated with Aβ deposits (Vargas et al.,
The authors also suggest that Aβ is involved in cell death pathway in choroid plexus since results from our group showed that Aβ-treated choroid plexus epithelial cells have an increased expression of caspases 3 and 9 (Vargas et al.,
The structure and location of the choroid plexus allows it for the distribution of molecules throughout the CSF and to the brain parenchyma as well as locally. This ventricular structure possesses a multitude of specific transporters and receptors and many biologically active compounds are produced at the choroid plexus, including a large number of neuropeptides, growth factors, and cytokines (Stopa et al.,
Within the list of choroid plexus related proteins, the expression of a vast range of them is significantly diminished in AD, including vascular endothelial growth factor (VEGF; Spuch et al.,
As previously reported, the choroid plexus regulates the transport of many growth factors, including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), VEGF, insulin, and insulin-like growth factor (IGF-I). In the case of IGF-I, megalin is involved in IGF-I transport from blood into the brain, and a decrease in megalin would result in low IGF-I input to the brain (Carro et al.,
In this review we have proposed that choroid plexus dysfunction can be a major contributing factor to the pathology of AD. Pathogenic processes such as mitochondrial activity deficits, oxidative stress, and morphological structural changes contribute to the decreased efficacy of the choroid plexus in clearing of Aβ, thus resulting in an Aβ accumulation in the brain. This in turn induces further pathological cascades of toxicity, inflammation, and neurodegeneration and may feedback to further enhance the disease process.
To date, the therapeutic targets have focused on diminishing the Aβ burden. However, we propose that targeting the upstream events such as mitochondrial deficits and oxidative stress as well as the choroid plexus carrier proteins (megalin, gelsolin) may prove to be more effective. Also, given that the choroid plexus itself has the ability to produce a nutritive “cocktail” of neurotrophic factors, there is evidence indicating that transplanted choroid plexus epithelial cells may potentially be used to protect neurons from excitotoxic damage (Emerich et al.,
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.