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Role of Cytoskeletal Elements in Regulation of Synaptic Functions: Implications Toward Alzheimer’s Disease and Phytochemicals-Based Interventions

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Harkomal Verma
Harkomal Verma
Harkomal Verma
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Sharanjot Kaur
Sharanjot Kaur
Sharanjot Kaur
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Sukhchain Kaur at Central University of Punjab
Sukhchain Kaur
Prabhakar Gangwar
Prabhakar Gangwar
Prabhakar Gangwar
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Abstract and Figures

Alzheimer’s disease (AD), a multifactorial disease, is characterized by the accumulation of neurofibrillary tangles (NFTs) and amyloid beta (Aβ) plaques. AD is triggered via several factors like alteration in cytoskeletal proteins, a mutation in presenilin 1 (PSEN1), presenilin 2 (PSEN2), amyloid precursor protein (APP), and post-translational modifications (PTMs) in the cytoskeletal elements. Owing to the major structural and functional role of cytoskeletal elements, like the organization of axon initial segmentation, dendritic spines, synaptic regulation, and delivery of cargo at the synapse; modulation of these elements plays an important role in AD pathogenesis; like Tau is a microtubule-associated protein that stabilizes the microtubules, and it also causes inhibition of nucleo-cytoplasmic transportation by disrupting the integrity of nuclear pore complex. One of the major cytoskeletal elements, actin and its dynamics, regulate the dendritic spine structure and functions; impairments have been documented towards learning and memory defects. The second major constituent of these cytoskeletal elements, microtubules, are necessary for the delivery of the cargo, like ion channels and receptors at the synaptic membranes, whereas actin-binding protein, i.e., Cofilin’s activation form rod-like structures, is involved in the formation of paired helical filaments (PHFs) observed in AD. Also, the glial cells rely on their cytoskeleton to maintain synaptic functionality. Thus, making cytoskeletal elements and their regulation in synaptic structure and function as an important aspect to be focused for better management and targeting AD pathology. This review advocates exploring phytochemicals and Ayurvedic plant extracts against AD by elucidating their neuroprotective mechanisms involving cytoskeletal modulation and enhancing synaptic plasticity. However, challenges include their limited bioavailability due to the poor solubility and the limited potential to cross the blood–brain barrier (BBB), emphasizing the need for targeted strategies to improve therapeutic efficacy.
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Vol:.(1234567890)
Molecular Neurobiology (2024) 61:8320–8343
https://doi.org/10.1007/s12035-024-04053-3
REVIEWS
Role ofCytoskeletal Elements inRegulation ofSynaptic Functions:
Implications Toward Alzheimer’s Disease andPhytochemicals‑Based
Interventions
HarkomalVerma1· SharanjotKaur2· SukhchainKaur2· PrabhakarGangwar1· MonishaDhiman2·
AnilKumarMantha1
Received: 3 July 2023 / Accepted: 13 February 2024 / Published online: 16 March 2024
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024
Abstract
Alzheimer’s disease (AD), a multifactorial disease, is characterized by the accumulation of neurofibrillary tangles (NFTs)
and amyloid beta (Aβ) plaques. AD is triggered via several factors like alteration in cytoskeletal proteins, a mutation in
presenilin 1 (PSEN1), presenilin 2 (PSEN2), amyloid precursor protein (APP), and post-translational modifications (PTMs)
in the cytoskeletal elements. Owing to the major structural and functional role of cytoskeletal elements, like the organiza-
tion of axon initial segmentation, dendritic spines, synaptic regulation, and delivery of cargo at the synapse; modulation of
these elements plays an important role in AD pathogenesis; like Tau is a microtubule-associated protein that stabilizes the
microtubules, and it also causes inhibition of nucleo-cytoplasmic transportation by disrupting the integrity of nuclear pore
complex. One of the major cytoskeletal elements, actin and its dynamics, regulate the dendritic spine structure and functions;
impairments have been documented towards learning and memory defects. The second major constituent of these cytoskeletal
elements, microtubules, are necessary for the delivery of the cargo, like ion channels and receptors at the synaptic membranes,
whereas actin-binding protein, i.e., Cofilin’s activation form rod-like structures, is involved in the formation of paired helical
filaments (PHFs) observed in AD. Also, the glial cells rely on their cytoskeleton to maintain synaptic functionality. Thus,
making cytoskeletal elements and their regulation in synaptic structure and function as an important aspect to be focused
for better management and targeting AD pathology. This review advocates exploring phytochemicals and Ayurvedic plant
extracts against AD by elucidating their neuroprotective mechanisms involving cytoskeletal modulation and enhancing syn-
aptic plasticity. However, challenges include their limited bioavailability due to the poor solubility and the limited potential
to cross the blood–brain barrier (BBB), emphasizing the need for targeted strategies to improve therapeuticefficacy.
Keywords Neurodegeneration· Alzheimer’s disease· Cytoskeletal elements· Microtubule· Microfilament· Synaptic
functionality· Phytochemicals
Introduction
Alzheimer’s disease (AD) is a complex neurological disor-
der involving alterations in various cellular processes such as
oxidative stress, inflammation, metabolic process, synaptic
function, and blood–brain barrier (BBB) [1]. The complexity
of various processes and their interlinking between them has
made it challenging to address their pathophysiology, and
thus, treatment strategies. Cytoskeletal elements viz micro-
tubules, intermediate filaments, and microfilaments are the
important structural and functional proteins in a neuron—
from maintaining neuronal polarity to axon formation and
synaptic regulation, are dysregulated at the structural and
functional level in AD [2, 3]. The AD brain shows higher
Harkomal Verma and Sharanjot Kaur contributed equally to this
work.
* Anil Kumar Mantha
anil.mantha@cup.edu.in
1 Department ofZoology, School ofBasic Sciences, Central
University ofPunjab, Village Ghudda, VPO – Ghudda,
Bathinda151401, Punjab, India
2 Department ofMicrobiology, School ofBasic Sciences,
Central University ofPunjab, Village Ghudda, Bathinda,
Punjab, India
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
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