Abstract
Aquaporin-4 (AQP4) is located mainly in the astrocytic end-feet around cerebral blood vessels and regulates ion and water homeostasis in the brain. While deletion of AQP4 is shown to reduce amyloid-β (Aβ) clearance and exacerbate Aβ peptide accumulation in plaques and vessels of Alzheimer’s disease mouse models, the mechanism and clearing pathways involved are debated. Here, we investigated how inhibiting the function of AQP4 in healthy male C57BL/6 J mice impacts clearance of Aβ40, the more soluble Aβ isoform. Using two-photon in vivo imaging and visualizing vessels with Sulfurodamine 101 (SR101), we first showed that Aβ40 injected as a ≤ 0.5-μl volume in the cerebral cortex diffused rapidly in parenchyma and accumulated around blood vessels. In animals treated with the AQP4 inhibitor TGN-020, the perivascular Aβ40 accumulation was significantly (P < 0.001) intensified by involving four times more vessels, thus suggesting a generalized clearance defect associated with vessels. Increasing the injecting volume to ≥ 0.5 ≤ 1 μl decreased the difference of Aβ40-positive vessels observed in non-treated and AQP4 inhibitor-treated animals, although the difference was still significant (P = 0.001), suggesting that larger injection volumes could overwhelm intramural vascular clearance mechanisms. While both small and large vessels accumulated Aβ40, for the ≤ 0.5-μl volume group, the average diameter of the Aβ40-positive vessels tended to be larger in control animals compared with TGN-020-treated animals, although the difference was non-significant (P = 0.066). Using histopathology and ultrastructural microscopy, no vascular structural change was observed after a single massive dose of TGN-020. These data suggest that AQP4 deficiency is directly involved in impaired Aβ brain clearance via the peri-/para-vascular routes, and AQP4-mediated vascular clearance might counteract blood-brain barrier abnormalities and age-related vascular amyloidopathy.
Highlights
While high levels of the soluble amyloid β-peptide (Aβ) isoform precipitate in the blood vessels walls as cerebral amyloid angiopathy (CAA) and directly contribute to the cognitive decline [15, 16], Aβ42 is the main component of the senile plaques found in Alzheimer disease (AD) [17]
With up to 50% of the Aβ being cleared across the blood-brain barrier (BBB) [18], it seems that investigating the mechanism by which Aβ is cleared needs a more careful consideration, especially in respect to Aβ40 and Aβ42 isoforms
Blood vessels were visible after systemic administration of SR 101
Summary
The histopathological hallmark of Alzheimer disease (AD) is represented by the accumulation of amyloid β-peptide (Aβ) plaques and neurofibrillary tangles generated by abnormally phosphorylated tau protein in the cortex of patients and is significantly associated with neurovascular dysfunction and neuronal loss [1, 2]. While LOAD is classically seen as an end-of-life pathology, careful epidemiological analysis suggests that young and/or middle life exposer to certain risk factors, namely, activity and cardiovascular performance, poor diet with major emphasis on insulin resistance, and even depression, impacts patient outcome and might lead to an earlier onset of disease [5,6,7] This raises more questions about the exact mechanism by which Aβ causes AD with several competing theories currently being researched, such as a direct toxicity of Aβ and its isoforms [8,9,10], a pro-oxidative stress shift in the brain [11, 12], a direct receptor interference, and mitochondrial dysfunction—all leading to synaptic dysfunction and neuronal loss [10, 13, 14]. Aβ40 is the major isoform shown to be cleared through and along vascular route (reviewed in [19])
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