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Alterations in Immune Responses Are Associated with Dysfunctional Intracellular Signaling in Peripheral Blood Mononuclear Cells of Men and Women with Mild Cognitive Impairment and Alzheimer’s disease

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Abstract

Deficits in the neuroendocrine-immune network in the periphery associated with the onset and progression of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) have not been extensively studied. The present study correlatively examines the association between cell-mediated immune responses, stress hormones, amyloid precursor protein (APP) expression, peripheral blood mononuclear cells (PBMC), and intracellular signaling molecules in the pathophysiology of MCI and AD compared to adults. Serum APP, lymphocyte proliferation, total cholinesterase (TChE), butyrylcholinesterase (BChE) activities, cytokines (IL-2, IFN-γ, IL-6, and TNF-α), and intracellular signaling molecules (p-ERK, p-CREB, and p-Akt) were measured in the PBMCs of adult, old, MCI, and AD men and women initially and after 3 years in the same population. An age- and disease-associated decline in mini-mental state examination (MMSE) scores and lymphocyte proliferation of MCI and AD men and women were observed. An age- and disease-related increase in serum APP, cortisol levels, and TChE activity were observed in men and women. Enhanced production of Th1 cytokine, IL-2, pro-inflammatory cytokines, and suppressed intracellular transcription factors may promote the inflammatory environment in MCI and AD patients. The expression of CREB and Akt was lower in MCI and AD men, while the expression of p-ERK was higher, and p-CREB was lower in MCI and AD women after 3 years. These results suggest that changes in specific intracellular signaling pathways may influence alterations in cell-mediated immunity to promote disease progression in MCI and AD patients.

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Data Availability

The datasets generated during and or analyzed are available from the corresponding author on request.

Abbreviations

AD:

Alzheimer’s disease

Akt:

Protein kinase B

APP:

Amyloid precursor protein

Aβ:

Amyloid beta

BBB:

Blood-brain barrier

BChE:

Butyrylcholinesterase

CNS:

Central nervous system

Con A:

Concanavalin A

CREB:

CAMP response element-binding protein

ERK:

Extracellular signal-regulated kinase

GSK3:

Glycogen synthase kinase 3

HDL:

High-density lipoprotein

HPA:

Hypothalamic-pituitary-adrenal

HRP:

Horseradish peroxidase

JNK:

C-Jun N-terminal kinase

LDL:

Low-density lipoprotein

MAPK:

Mitogen-activated protein kinase

MCI:

Mild cognitive impairment

MMSE:

Mini-mental state examination

NFT:

Neurofibrillary tangle

PBMC:

Peripheral blood mononuclear cells

TChE:

Total cholinesterase

TGF-β:

Transforming growth factor-β

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Acknowledgements

We thank the study volunteers, caregivers, and physicians, T. Swarnalingam MD, T. Sripriya MBBS, DNB, Ph. D., D. Killivalavan, MBBS, S. Madhumalar, MD, N. Rajkumar, MBBS, A. Pushparani, MD, M. Buvana, MS, and T. Prakash, MD for their assistance in the data collection and C. Thyagarajan, Sushruth S, Soha Chaya, T. Kannan, Mantavya Patel, Shaili Gour, R. Kishore Aravind, and Sunil Karrunanithi for their technical assistance.

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Authors and Affiliations

  1. Integrative Medicine Laboratory, Department of Biotechnology, SRM Institute of Science & Technology, Kattankulathur, 603203, Tamil Nadu, India

    Ramasamy Vasantharekha, Lalgi Hima, Uday P. Pratap & Srinivasan ThyagaRajan

  2. Institute of Advanced Research in Health Sciences, Tamil Nadu Government Multi Super Speciality Hospital, Omandurar Government Estate, Chennai, Tamil Nadu, India

    Hannah P. Priyanka & Rahul S. Nair

  3. Department of Neurology, Tamil Nadu Dr. M.G.R Medical University, Chennai, India

    Avathvadi V. Srinivasan

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  1. Ramasamy Vasantharekha
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Contributions

All authors contribute to the study’s conception and design. Material preparation, data collection, and data analysis were performed by RV, UP, and LH. The first draft of the manuscript was fully written by RV, edited by RN, HP, and STR, and supervised by AVS and STR. All authors read and approved the final manuscript.

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Correspondence to Ramasamy Vasantharekha.

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This study was performed in line with the principles of the Declaration of Helsinki Approval was granted by the Ethics Committee of SRM Medical College Hospital and Research Centre, Kattankulathur, (66 /IEC/2010).

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Vasantharekha, R., Priyanka, H.P., Nair, R.S. et al. Alterations in Immune Responses Are Associated with Dysfunctional Intracellular Signaling in Peripheral Blood Mononuclear Cells of Men and Women with Mild Cognitive Impairment and Alzheimer’s disease. Mol Neurobiol 61, 2964–2977 (2024). https://doi.org/10.1007/s12035-023-03764-3

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