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Molecular Insights to the Wnt Signaling During Alzheimer’s Disorder: a Potential Target for Therapeutic Interventions

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Abstract

In the adult brain, Wnt signaling is crucial for neurogenesis, and it also regulates neuronal development, neuronal maturation, neuronal differential, and proliferation. Impaired Wnt signaling pathways are associated with enhanced levels of amyloid-β, reduced β-catenin levels, and increased expression of GSK-3β enzyme, suggesting its direct association with the pathogenesis of Alzheimer’s disorder (AD). These findings are consolidated by reports where activation of Wnt signaling by genetic factors and pharmacological intervention has improved the cognitive functions in animals and restored neurogenesis in the adult brain. Various natural and synthetic molecules have been identified that modulate Wnt signaling in the adult brain and promote neurogenesis and alleviate behavioral dysfunction. These molecules include lithium, valproic acid, ethosuximide, selenomethionine, curcumin, andrographolide, xanthoceraside, huperzine A, pyridostigmine, ginkgolide-B, ricinine, cannabidiol, and resveratrol. These molecules are associated with the DKK1 and GSK-3β inhibition and β-catenin stabilization along with their effects on neurogenesis, neuronal proliferation, and differentiation in the hippocampus through modulation of Wnt signaling and thereby could prove beneficial in the management of AD pathogenesis. Although modulation of the Wnt signaling seems to suggest to be promising in the management of AD, unfortunately, most of the literature available for the association of Wnt signaling and AD pathogenesis is either from preclinical studies or post-mortem brain. Therefore, it will be interesting to understand the role of Wnt signaling in AD patients, and a rigorous investigation could provide us with a better understanding of AD pathogenesis and the identification of novel targets for therapeutic interventions.

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Abbreviations

Wnt:

Wingless-type integration site

AD:

Alzheimer’s disorder

Wg:

Wingless

Int:

Integration

PCP:

Planar cell polarity

CNS:

Central nervous system

βA:

β-Amyloid

NFT:

Neurofibrillary tangles

GSK-3 β:

Glycogen synthase kinase-3 beta

DKK:

Dickkopf

Fzz:

Frizzled

LRP:

Lipoprotein receptor-related protein

Wnt-Fzz-LRP:

Wnt receptor complex

APC:

Adenomatous polyposis coli gene

CK-1α:

Casein kinase-1- alpha

Dvl:

Dishevelled

TCF:

T cell-specific transcription factor

LEF:

Lymphoid enhancer-binding factor

JNK:

Jun N-terminal kinase

DAG:

Diacylglycerol

IP3:

Inositol triphosphate

PKC:

Protein kinase C

NF-AT:

Nuclear factor of activated T cells

PLC :

Phospholipase C

ROCK:

Rho-associated kinase

Sfrp:

Secreted frizzled-related protein

Krm-2:

Kremen-2

IGFBP-4:

Insulin-like growth factor-binding protein-4

WIF-1 :

Wnt-inhibitory factor-1

BBB :

Blood–brain barrier

Glut1:

Glucose transporter 1

PSEN:

Presenilin

NeuroD1:

Neuronal differentiation 1

AHPs:

Adult hippocampal progenitors

CaMKII:

Calmodulin-dependent protein kinase I

TREM2:

Triggering receptor expressed on myeloid cells 2

WASP-1:

Wnt-activating small molecule potentiator-1

NPCs:

Neural progenitor cells

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Acknowledgements

The authors would like to acknowledge the Government College of Pharmacy Rohru, SJJT University Rajasthan, and Chitkara University Punjab for supporting this work.

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Authors and Affiliations

  1. Department of Pharmacy, Shri Jagdishprasad Jhabarmal Tibrewala University, Jhunjhunu, Rajasthan, India

    Priyanka Nagu & Amjad Khan A. Pathan

  2. Department of Pharmaceutics, Government College of Pharmacy, Rohru, Himachal Pradesh, India

    Priyanka Nagu

  3. Chitkara College of Pharmacy, Chitkara University, Punjab, India

    Vivek Sharma & Tapan Behl

  4. Department of Pharmacology, Government College of Pharmacy, Himachal Pradesh 171207, Rohru, District Shimla, India

    Vivek Sharma & Vineet Mehta

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  1. Priyanka Nagu
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  4. Amjad Khan A. Pathan
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  5. Vineet Mehta
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PN drafted the manuscript and was involved in designing and finalizing the image/s. VS contributed to critical analysis, editing, and multiple revisions and provided expert inputs. TB contributed to critical analysis, editing, and multiple revisions of the manuscript. AKP contributed editing and provided crucial technical inputs to the manuscript. VM designed, wrote, drafted, and edited the manuscript. All authors approved the final version as submitted.

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Correspondence to Vineet Mehta.

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Nagu, P., Sharma, V., Behl, T. et al. Molecular Insights to the Wnt Signaling During Alzheimer’s Disorder: a Potential Target for Therapeutic Interventions. J Mol Neurosci 72, 679–690 (2022). https://doi.org/10.1007/s12031-021-01940-5

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