Pathogenesis of Alzheimer’s disease: Involvement of the Choroid Plexus

Abstract

Alzheimer's disease is a neurodegenerative disorder characterized clinically by cognitive decline and pathologically by amyloid deposition and neurofibrillary changes. These neuropathological hallmarks are accompanied by reactive events including microglial activation and astrogliosis. The inflammatory response in Alzheimer's disease brains is distinguished by a pro-inflammatory signature involving amyloid peptides, inflammasome signalling and disrupted blood brain barrier. Inflammatory changes are observed also in the cerebrospinal fluid in Alzheimer's disease. It remains unknown, however, whether the choroid plexus which produces cerebrospinal fluid and guards the brain from peripheral inflammatory insults, contributes to the inflammation and pathogenesis of Alzheimer's disease. Here we show that the choroid plexus in Alzheimer's disease exhibits a pro-inflammaotory signature with aberrant protein accumulation, which contribute to the age-dependent inflammatory changes observed in the cerebrospinal fluid. Magnetic resonance imaging reveals that the choroid plexus in patients with Alzheimer's disease displays pathological signal and increased volume, which inversely correlates with cognitive decline. Our findings suggest that the choroid plexus, being unable to efficiently resolve inflammatory insults over the lifetime, eventually ignites and drives the aberrant inflammatory response observed in Alzheimer's disease. These findings advance our understanding of the pathogenesis and open new vistas in the diagnostics and therapeutics of Alzheimer's disease.

Longitudinal progression of choroid plexus enlargement is associated with female sex, cognitive decline and ApoE E4 homozygote status

“…This hypothesis was further explored by considering diagnostic group × CP volume associations. In agreement with previous studies (35)(36)(37), we found larger CP volume at baseline in subjects with dementia, as compared to stable CN (Tables 1B, 2). However, due to our longitudinal study design, we were able to additionally include a group of convertors, which also exhibited a baseline difference from CN, showing further CP increase with cognitive impairment.…”

“…CP-mediated neuroinflammation has been suggested as a possible pathophysiological mechanism of AD and other neurodegenerative diseases ( 11 , 12 ) and corroborated by reversal of AD-related cognitive decline and beta-amyloid deposition after introduction of CP targeted immune-suppression ( 38 ). CP inflammation was also linked to increased CP volume and remodeling in AD ( 36 ). Although sex differences in CP immunologic activity in cognitive impairment have to our knowledge not been directly explored, immune mechanisms in AD show significant and complex interactions with sex, with generally, but not exclusively, higher pro-inflammatory activity in females ( 18 , 22 , 23 , 54 , 55 ).…”

“…In the context of Alzheimer’s disease, choroid plexus has been described to undergo other changes which could contribute to its increased volume, such as basal membrane thickening and complex remodeling including beta amyloid deposition ( 11 , 15 , 36 , 62 ). ApoE accumulation in CP in the form of lipofuscin or complex filamentous structures with lipid droplets has also been described ( 63 ), providing another potential link between ApoE E4 and CP enlargement.…”

“…CP enlargement has been linked with neuroinflammation in multiple sclerosis in both animals and human subjects (7). An increase in CP volume has been noted in ageing (25), and disease states linked with inflammation, such as complex regional pain (26), psychosis and schizophrenia (27,28), depression (29), stroke (30), multiple sclerosis (31-33), obesity (34), and cross-sectionally in AD (35)(36)(37). Choroid plexus-mediated mechanisms represent potential promising targets for future treatments based on animal models of AD (38).…”