Therapies Which Enhance PLCG2 Activity May Be Effective in Treating Parkinson and Alzheimer Diseases

Jessica Nye, PhD
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Benzodiazepines and related drugs frequently used before and after diagnosis of Alzheimer's disease
Benzodiazepines and related drugs frequently used before and after diagnosis of Alzheimer’s disease
The study authors sought to determine which components of the peripheral immune response correlated with diagnoses of Alzheimer or Parkinson Disease.

Patients with Alzheimer disease (AD) may benefit from therapies which enhance 1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase gamma-2 (PLCG2) activity. These findings were published in Science Advances.

Patients and controls (N=132) were recruited at Stanford University for this mass cytometric study of peripheral blood mononuclear cells (PBMCs). Participants were split into discovery and validation cohorts. The discovery group consisted of patients with AD (n=28), Parkinson disease (PD) (n=17), healthy controls aged >60 years (HC-I; n=53), and healthy controls aged £50 years (HC-II; n=10). The validation cohort included patients with AD (n=9) and healthy controls aged >60 years (n=15).

PBMCs extracted from whole blood were either unstimulated or stimulated with 7 canonical immune stimulants before undergoing time-of-flight mass cytometry which assessed cell subsets, protein expression, and single-cell signaling pathway activation. A machine learning approach was used to discern the differences of immune features between cases and controls.

Among the PBMCs, the investigators detected 24 communities of networks. Using these correlated immune features, the immunological Elastic Net (iEN) algorithm was used to classify the validation cohort as AD or HC, the model was well fit with an area under the curve (AUC) of 0.84±0.08 (P =5.42×10-3).

Out of the 4200 immune feature components, 14 features with the highest magnitudes best indicated AD diagnosis risk. These 14 features comprised 4 communities of networks.

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A top network included phospho-PLCg2 (pPLCG2), which had differential signaling between AD and HC-I participants. AD patients had significantly decreased pPLCG2 response in unstimulated natural killer T cells (NKT; P =8.78×10-4), liposaccharide-stimulated NKT cells (P =7.47×10-4), and unstimulated CD56 NK cells (P =3.07×10-3).

Another top network included phospho-signal transducer and activator of transcription (pSTAT), in which response was decreased among AD patients for pSTAT1 response in interferon-a-stimulated plasmablasts (P =9.00×10-3) and pSTAT5 in interferon-a-stimulated CD4 cells (P =1.43×10-2).

Separated by sex, the investigators observed that pPLCG2 was driving the differential response among men and pSTATs among women. Separated by apolipoprotein allele type, pPLCG2 remained significant among both subtypes, indicating a significant relevance for both subgroups of AD.

Compared with HC-II, no networks differed for pPLCG2 activation and few network differences were due to pSTATs, indicating that the alterations of PLCG2 and STAT signaling among patients with AD was not due to the normal aging process.

The iEN model trained with AD data was able to predict PD with satisfactory performance (AUC, 0.88±0.06; P =1.75×10-6), indicating some disease overlap. These overlapping communities, however, did not include pSTATs or PLCG2.

This study was limited by the low sample sizes.

The study authors concluded reduced PLCG2 activity was a significant biomarker of the AD immune response which was independent of apolipoprotein subtype or the natural process of aging and may be a possible therapeutic target.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.

Reference

Phongpreecha T, Fernandez R, Mrdjen D, et al. Single-cell peripheral immunoprofiling of Alzheimer’s and Parkinson’s diseases. Sci Adv. 2020;6(48):eabd5575. doi:10.1126/sciadv.abd5575