AQP4 potentiator (mislocalization / amyloid / p-tau), Glymphatic system in PD, AQP4 SNP, Burfeind 2017 cohort, Target validation, Ariba procurement, Astrocyte start

AQP4 potentiator

(#1617)	row	content
	AQP4 mislocalization (dysfunction)	observed in AD patients
	Amyloid β clearance	A: ¹²⁵I-Amyloid β / HiLyte-555-Amyloid β intrastriate injection. Clearance plot of % of injected radioactivity vs Time (min) for WT vs Aqp4-/- shows clearance reduced by ~55% [49].

Increased amyloid accumulation in AQP4 KO × APP-PS1 mice (Mol Neurodegener. 2015, 10:58)

Multi-panel bar chart labels:

• C: Aβ plaque load stained by 6E10 (% area), Cortex / HC, APP/PS1 vs AQP4⁻/APP/PS1
• D: Aβ plaque load stained by thioflavin-S (% area), Cortex / HC
• E: 6E10-IR intensity on vessels, Parenchyma vs Pia matters
• F: Soluble Aβ40 (ng/g brain)
• G: Soluble Aβ42 (ng/g brain)
• H: Insoluble Aβ40 (ng/g brain)
• I: Insoluble Aβ42 (ng/g brain)

Exacerbation of p-tau accumulation and neuronal death in AQP4 KO × PS19 mice

(Prof. Iwatsubo lab, Tokyo Univ., at 38th Annual Meeting of Japan Society for Dementia Research, 2019)

9 mo. old PS19 ×	AQP4 (+/+)	AQP4 (-/-)
P-tau in Cortex	75%	↑90%
P-tau in Hippocampus	22%	↑50%
NeuN in Cortex	0.3 mm	↓0.18 mm
NeuN in Hippocampus	1.2 mm	↓0.7 mm

Glymphatic system in PD

		human	Animal
(Ding, 2021 #1527)	dynamic contrast-enhanced magnetic resonance imaging	iPD exhibited significantly reduced flow through the meningeal lymphatic vessels (mLVs) along the superior sagittal sinus and sigmoid sinus, as well as a notable delay in deep cervical lymph node perfusion, compared to patients with AP.	emergence of a -syn pathology was followed by delayed meningeal drainage, loss of tight junctions among meningeal lymphatic endothelia, increased inflammation of the meninges
(Donahue, 2021 #1528)		Human] There was a significant increase in global and regional PVS volume fraction in PD versus non-PD, particularly in FPD versus NMC. Regionally, FPD and NMC differed in the medial orbitofrontal region, as did LRRK2 FPD versus NMC. Non-PD and IPD differed in the cuneus and lateral occipital regions.

FIG. 1 caption: Perivascular space (PVS) volume fraction (%) across global cortical and subcortical white matter in (a) PD (Parkinson’s disease) versus (b) non-PD IPD (idiopathic PD), FPD (familial PD) individuals, NMCs (nonmanifest carriers), and HCs (healthy controls). Swarm plots of the present PVS data points and the second panels present the effect size as a bootstrap 95% confidence interval on an aligned axis, highlighting the effect size. Significance level: P<0.05 (), P<0.01 (), P<0.001 (), P<0.0001 (****). [Color figure can be viewed at wileyonlinelibrary.com]

Panel (a): nonPD N=185 vs PD N=246 swarm plots; PD minus nonPD Cohen’s d.

Panel (b): NMC N=101 / HC N=84 / FPD N=67 / IPD N=179 swarm plots; HC minus NMC, FPD minus NMC, IPD minus NMC Cohen’s d effect-size estimates.

SNP

(Chandra, 2021 #1533) 100 Aβ-positive patients with LMCI or mild AD, 469 Aβ-negative patients with MCI (either Aβ positive [n=¼ 8], or negative [n=¼ 145], or with no amyloid PET imaging [n=¼ 156]), and 244 patients with LMCI (either Ab positive[n=¼ 62], or negative [n=¼ 27] or with no amyloid PET imaging [n=¼ 155]).

AQP4 SNP minor-allele-carrier bar plot:

• x-axis SNPs: rs3875089, rs3763040, rs3763043, rs2075575, rs151244, rs72878794
• series: Aβ Negative Cognitively Normal vs Aβ Positive LMCI and AD
• y-axis: %Minor Allele Carrier

Fig. 3 caption: Frequency distribution depicting percentages of AQP4 minor allele carriers for Aβ-positive LMCI and AD patients (n=100) compared to Aβ-negative cognitively normal individuals (n=97).

SNP	behavior
rs72878794	decreased Ab uptake
rs151244	increased Ab uptake, increased risk of conversion from MCI (HR=1.39) and LMCI (HR=1.59) to AD, and an increased 4-year rate of ADAS-Cog decline in LMCI.

The final panel set consisted of five AQP4 SNPs: rs335929, rs3763043, rs3763040, rs9951307, and rs3875089.

None of the five SNPs were associated with different rates of AD diagnosis, age of dementia onset in trial subjects. No association between AQP4 SNPs with histological measures of AD pathology, including Braak stage or neuritic plaque density was observed. However, AQP4 SNPs were associated with altered rates of cognitive decline after AD diagnosis, with two SNPS (rs9951307 and rs3875089) associated with slower cognitive decline and two (rs3763040 and rs3763043) associated with more rapid cognitive decline after AD diagnosis.

(Burfeind, 2017 #1535) Of the participants, 471 did not receive AD diagnosis any time during the study, whereas received AD diagnosis at somepoint. Of 471 participants that did not receive AD diagnosis, 242 received a mild cognitive impairment (MCI) diagnosis at some point during the study

Questions

• Link: protein impact of rs151244 (ie ↓ expression?) functional impact (?)
• The magnitude of SNP : SSE
• SHOULD we focus on AD?
• In normal Level, still be effective?
• ↓ AQP4 level in PD?

Target validation

	SNP	Protein expression	In vitro	In vivo	Clinical
Target validation	rs151244	On astrocytic endfoot	Functional (osmotic, LDH)	• human in vivo • mouse model available? (AQP4 KO mice) (glymphatic flow, tau)	• Baseline tau load, • Disease severity (ADAS-cog, progression)

IBA / Ariba US

• https://s1.ariba.com/gb/?realm=takeda&locale=en_US
• 지급 여부 check: Ariba website → ‘your resequest’ → click the blue purchase order number → ‘View in SAP Ariba Procurement’ → Once payment happen, you can see “payment” right to “invoices”. → click on the blue code below ‘Transaction’ → ‘Payment Date’ (and ‘Amount Paid’)
• problem/Help/ticket: Procurement - Procurement Solutions Portal (service-now.com)

Astrocyte

• Glial cells (e.g., astrocytes, oligodendrocytes, and microglia) are in either a proliferative or non-proliferative state, depending on their differentiation status and possible re-entry into the cell cycle.
• Unlike neurons, astrocytes do not have Nissl substances in the cytoplasm (Li, 2019 #2281)