Abstract
Compromised secretory function of choroid plexus (CP) and defective cerebrospinal fluid (CSF) production, along with accumulation of beta-amyloid (Aβ) peptides at the blood-CSF barrier (BCSFB), contribute to complications of Alzheimer’s disease (AD). The AD triple transgenic mouse model (3xTg-AD) at 16 month-old mimics critical hallmarks of the human disease: β-amyloid (Aβ) plaques and neurofibrillary tangles (NFT) with a temporal- and regional- specific profile. Currently, little is known about transport and metabolic responses by CP to the disrupted homeostasis of CNS Aβ in AD. This study analyzed the effects of highly-expressed AD-linked human transgenes (APP, PS1 and tau) on lateral ventricle CP function. Confocal imaging and immunohistochemistry revealed an increase only of Aβ42 isoform in epithelial cytosol and in stroma surrounding choroidal capillaries; this buildup may reflect insufficient clearance transport from CSF to blood. Still, there was increased expression, presumably compensatory, of the choroidal Aβ transporters: the low density lipoprotein receptor-related protein 1 (LRP1) and the receptor for advanced glycation end product (RAGE). A thickening of the epithelial basal membrane and greater collagen-IV deposition occurred around capillaries in CP, probably curtailing solute exchanges. Moreover, there was attenuated expression of epithelial aquaporin-1 and transthyretin (TTR) protein compared to Non-Tg mice. Collectively these findings indicate CP dysfunction hypothetically linked to increasing Aβ burden resulting in less efficient ion transport, concurrently with reduced production of CSF (less sink action on brain Aβ) and diminished secretion of TTR (less neuroprotection against cortical Aβ toxicity). The putative effects of a disabled CP-CSF system on CNS functions are discussed in the context of AD.
Highlights
Alzheimer’s disease (AD) is age-related neurodegeneration characterized by plaques that consist mainly of amyloid-β (Aβ) peptides and neurofibrillary tangles (NFT) containing hyperphosphorylated tau protein
Increasing data for animals support the notion that compromised function of choroid plexus (CP) and defective cerebrospinal fluid (CSF) production and turnover (Chiu et al, 2012), with diminished clearance of the Aβ peptides normally produced in brain, may be a mechanism implicated in the exacerbation of sporadic AD (sAD) (Silverberg et al, 2001, 2003; Serot et al, 2003b; Johanson et al, 2008; Wostyn et al, 2011)
AMYLOID-BETA DISTRIBUTION IN CP OF 3xTg-AD AND NON-Tg MICE Aβ is a short peptide generated from amyloid precursor protein (APP) with two main breakdown products, Aβ peptides of 40 (Aβ40) and Aβ42
Summary
Alzheimer’s disease (AD) is age-related neurodegeneration characterized by plaques that consist mainly of amyloid-β (Aβ) peptides and neurofibrillary tangles (NFT) containing hyperphosphorylated tau protein. These protein distortions contribute to disrupted synapses and neurotransmission, progressive neuronal death, memory impairment, and cognitive disturbances (Church et al, 2014). Increasing data for animals support the notion that compromised function of CP and defective CSF production and turnover (Chiu et al, 2012), with diminished clearance of the Aβ peptides normally produced in brain, may be a mechanism implicated in the exacerbation of sAD (Silverberg et al, 2001, 2003; Serot et al, 2003b; Johanson et al, 2008; Wostyn et al, 2011). Because compromised metabolic functions of CP and defective CSF production (turnover) may be linked to worsening sAD, we decided to ascertain whether 3xTg-AD is useful to study the role of CP in AD
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