Aquaporin4 (AQP4) is a water channel protein located at astrocyte foot processes that plays a role in glymphatic system, a highly organized fluid transport pathway which seems to be involved in Alzheimer’s disease (AD) and normal pressure hydrocephalus (NPH) pathophysiology. Cerebrospinal fluid (CSF) AQP4 levels were determined in 11 patients with AD, 10 patients with NPH, and 9 controls. We found significantly reduced AQP4 in AD patients, a trend in reduction in NPH patients, and a correlation between AQP4 and amyloid-β CSF levels. This study indicates the potential role of AQP4 and glymphatic system in neurodegenerative diseases pathophysiology.
AuklandK, ReedRK (1993) Interstitial-lymphatic mechanisms in the control of extracellular fluid volume. Physiol Rev73, 1–78.
2.
Schmid-SchönbeinGW (1990) Microlymphatics and lymph flow. Physiol Rev70, 987–1028.
3.
Casley-SmithJR, Foldi-BorcsokE, FoldiM (1976) The prelymphatic pathways of the brain as revealed by cervical lymphatic obstruction and the passage of particles. Br J Exp Pathol57, 179–188.
4.
RennelsML, GregoryTF, BlaumanisOR, FujimotoK, GradyPA (1985) Evidence for a ‘paravascular’ fluid circulation in the mammalian central nervous system, provided by the rapid distribution of tracer protein throughout the brain from the subarachnoid space. Brain Res326, 47–63.
5.
CserrHF, CooperDN, MilhoratTH (1977) Flow of cerebral interstitial fluid as indicated by the removal of extracellular markers from rat caudate nucleus. Exp Eye Res25, 461–473.
6.
IliffJJ, WangM, LiaoY, PloggBA, PengW, GundersenGA, BenvenisteH, VatesGE, DeaneR, GoldmanSA, NagelhusEA, NedergaardM (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med4, 147ra11.
RasmussenMK, MestreH, NedergaardM (2018) The glymphatic pathway in neurological disorders. Lancet Neurol17, 1016–1024.
9.
XuZ, XiaoN, ChenY, HuangH, MarshallC, GaoJ, CaiZ, WuT, HuG, XiaoM (2015) Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits. Mol Neurodegener10, 58.
10.
KressBT, IliffJJ, XiaM, WangM, WeiHS, ZeppenfeldD, XieL, KangH, XuQ, LiewJA, PlogBA, DingF, DeaneR, NedergaardM (2014) Impairment of paravascular clearance pathways in the aging brain. Ann Neurol76, 845–861.
11.
WangJ, GuBJ, MastersCL, WangYJ (2017) A systemic view of Alzheimer disease—insights from amyloid-β metabolism beyond the brain. Nat Rev Neurol13, 612–623.
12.
ZeppenfeldDM, SimonM, HaswellJD, D’AbreoD, MurchisonC, QuinnJF, GrafeMR, WoltjerRL, KayeJ, IliffJJ (2017) Association of perivascular localization of aquaporin-4 with cognition and Alzheimer disease in aging brains. JAMA Neurol74, 91–99.
13.
WilcockDM, VitekMP, ColtonCA (2009) Vascular amyloid alters astrocytic water and potassium channels in mouse models and humans with Alzheimer’s disease. Neuroscience159, 1055–1069.
14.
SkucasVA, MathewsIB, YangJ, ChengQ, TreisterA, DuffyAM, VerkmanAS, HempsteadBL, WoodMA, BinderDK, ScharfmanHE (2011) Impairment of select forms of spatial memory and neurotrophin-dependent synaptic plasticity by deletion of glial aquaporin-4. J Neurosci31, 6392–6397.
15.
WikkelsøC, HellströmP, KlingePM, TansJT, European iNPH Multicentre Study Group (2013) The European iNPH Multicentre Study on the predictive values of resistance to CSF outflow and the CSF Tap Test in patients with idiopathic normal pressure hydrocephalus. J Neurol Neurosurg Psychiatry84, 562–568.
16.
RingstadG, VatneholSAS, EidePK (2017) Glymphatic MRI in idiopathic normal pressure hydrocephalus. Brain140, 2691–2705.
17.
RingstadG, ValnesLM, DaleAM, PrippAH, VatneholSS, EmblemKE, MardalKA, EidePK (2018) Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. JCI Insight3, 121537.
18.
EidePK, HanssonHA (2018) Astrogliosis and impaired aquaporin-4 and dystrophin systems in idiopathic normal pressure hydrocephalus. Neuropathol Appl Neurobiol44, 474–490.
19.
LeinonenV, KoivistoAM, SavolainenS, RummukainenJ, TamminenJN, TillgrenT, VainikkaS, PyykkoOT, MolsaJ, FraunbergM, PirttilaT, JaaskelainenJE, SoininenH, RinneJ, AlafuzoffI (2010) Amyloid and tau proteins in cortical brain biopsy and Alzheimer’s disease. Ann Neurol68, 446–453.
20.
GolombJ, WisoffJ, MillerDC, BoksayI, KlugerA, WeinerH, SaltonJ, GravesW (2000) Alzheimer’s disease comorbidity in normal pressure hydrocephalus: Prevalence and shunt response. J Neurol Neurosurg Psychiatry68, 778–781.
21.
ShprecherD, SchwalbJ, KurlanR (2008) Normal pressure hydrocephalus: Diagnosis and treatment. Curr Neurol Neurosci Rep8, 371–376.
22.
SantangeloR, CecchettiG, BernasconiMP, CardamoneR, BarbieriA, PintoP, PasseriniG, ScomazzoniF, ComiG, MagnaniG (2017) Cerebrospinal fluid amyloid-β 42, total tau and phosphorylated tau are low in patients with normal pressure hydrocephalus: analogies and differences with Alzheimer’s disease. J Alzheimers Dis60, 183–200.
ReisbergB, FerrisSH, de LeonMJ, CrookT (1982) The Global Deterioration Scale for assessment of primary degenerative dementia. Am J Psychiatry139, 1136–1139.
25.
MarmarouA, BergsneiderM, KlingeP, RelkinN, BlackPM (2005) The value of supplemental prognostic tests for the preoperative assessment of idiopathic normal-pressure hydrocephalus. Neurosurgery57(3 Suppl), S17–S28.
26.
RaneriF, ZellaMAS, Di CristoforiA, ZarinoB, PluderiM, SpagnoliD (2017) Supplementary tests in idiopathic normal pressure hydrocephalus: a single-center experience with a combined lumbar infusion test and tap test. World Neurosurg100, 567–574.
27.
CabralD, BeachTG, VeddersL, SueLI, JacobsonS, MyersK, SabbaghMN (2011) Frequency of Alzheimer’s disease pathology at autopsy in patients with clinical normal pressure hydrocephalus. Alzheimers Dement7, 509–513.
28.
LocatelliM, DraghiR, DI CristoforiA, CarrabbaG, ZavanoneM, PluderiM, SpagnoliD, RampiniP (2014) Third ventriculostomy in late-onset idiopathic aqueductal stenosis treatment: a focus on clinical presentation and radiological diagnosis. Neurol Med Chir (Tokyo)54, 1014–1021.
29.
TsaiA, Malek-AhmadiM, KahlonV, SabbaghMN (2014) Differences in cerebrospinal fluid biomarkers between clinically diagnosed idiopathic normal pressure hydrocephalus and Alzheimer’s disease. J Alzheimers Dis Park4, pii: 1000150.
30.
KapakiEN, ParaskevasGP, TzerakisNG, SfagosC, SeretisA, KararizouE, VassilopoulosD (2007) Cerebrospinal fluid tau, phospho-tau181 and beta-amyloid1-42 in idiopathic normal pressure hydrocephalus: A discrimination from Alzheimer’s disease. Eur J Neurol14, 168–173.
31.
Agren-WilssonA, LekmanA, SjobergW, RosengrenL, BlennowK, BergenheimAT, MalmJ (2007) CSF biomarkers in the evaluation of idiopathic normal pressure hydrocephalus. Acta Neurol Scand116, 333–339.
32.
JingamiN, Asada-UtsugiM, UemuraK, NotoR, Taka- hashiM, OzakiA, KiharaT, KageyamaT, TakahashiR, ShimohamaS, KinoshitaA (2015) Idiopathic normal pressure hydrocephalus has a different cerebrospinal fluid biomarker profile from Alzheimer’s disease. J Alzheimers Dis45, 109–115.
33.
MoriyaM, MiyajimaM, NakajimaM, OginoI, AraiH (2015) Impact of cerebrospinal fluid shunting for idiopathic normal pressure hydrocephalus on the amyloid cascade. PLoS One10, e0119973.
34.
MiyajimaM, NakajimaM, OginoI, MiyataH, MotoiY, AraiH (2013) Soluble amyloid precursor protein in the cerebrospinal fluid as a diagnostic and prognostic biomarker for idiopathic normal pressure hydrocephalus. Eur J Neurol20, 236–242.
35.
RayB, ReyesPF, LahiriDK (2011) Biochemical studies in normal pressure hydrocephalus (NPH) patients: Change in CSF levels of amyloid precursor protein (APP), amyloid-beta (Aβ) peptide and phospho-tau. J Psychiatr Res45, 539–547.
36.
TullbergM, BlennowK, ManssonJE, FredmanP, TisellM, WikkelsoC (2007) Ventricular cerebrospinal fluid neurofilament protein levels decrease in parallel with white matter pathology after shunt surgery in normal pressure hydrocephalus. Eur J Neurol14, 248–254.
