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International Journal of Bioprinting 3D model of neurogenesis in Alzheimer’s disease

the hippocampus is involved in memory and learning, Bioprinting has emerged as a highly promising tool
1
most studies involving neurogenesis in Alzheimer’s for neurobiology, offering a technological approach to
disease (AD) primarily focus on this niche, noting that tailor 3D constructs effectively. 17–19 Moreover, bioprinting
2–5
neurogenesis decreases mainly due to amyloid beta (Aβ) enables the creation of volumetric, biomimetic
aggregation and senile plaque formation. microenvironments that can emulate specific events
of the central nervous system (CNS). By designing
20
However, recent studies have demonstrated that
alterations in adult SVZ neurogenesis also play a crucial specific combinations of cells and hydrogel that mimic the
extracellular matrix environment, neurogenic niches, and
role in AD. 6–10 Transplantation of SVZ-derived newborn other areas of the brain, specific microstructures can be
neurons can restore impaired neural circuits, which potentially bioprinted. 17,21–25
compensates for the reduced neuronal population found
in AD, playing a pivotal role in cognitive function and Therefore, bioprinting is at the forefront of elucidating
11
disease pathogenesis. Moreover, by undefined pathways, NSC behavior by studying distinct areas, such as retina
26
neurogenesis in the SVZ may be regulated and stimulated recreation by stem cell transplantation; toxicological
by Aβ in young adult animals. Despite all evidence, performance of compounds, such as cannabidiol, on
12
there is a lack of studies focusing on the role of adult SVZ neuroprogenitor cells; modeling neural tissue using
27
neurogenesis in AD. induced pluripotent stem cells (iPSCs) and iPSC-
derived NSCs; evaluation of neural regeneration; and
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29
The contribution of Aβ to AD initiation and recapitulating areas of damaged CNS tissue. 30
progression is highly complex; it participates in different
cellular events depending on the peptide’s aggregation Although this technological tool is very promising,
state, concentration, and the brain’s developmental stage. there is a lack of studies involving modeling and
Aβ can either impair the brain’s homeostatic balance, bioprinting neurodegenerative conditions, especially
as in AD, or play a role in normal brain development, reproducing and biomimicking NSCs in AD. In this study,
by inducing NSC self-renewal and differentiation into we developed and characterized a 3D model of the adult
neurons, astrocytes, and oligodendrocytes. Aβ peptides SVZ-NSC environment in AD by bioprinting NSC-derived
13
are generated by enzymatic cleavage of amyloid precursor neurospheres from six-week-old wild-type mice in a bioink
protein (APP) in the plasma membrane of neurons and containing Aβ oligomers. The biomaterial we produced and
glial cells. Two distinct pathways lead to APP cleavage: standardized may serve as a platform to further develop
(i) the non-amyloidogenic pathway that results in the novel therapeutic strategies, also contributing to providing
formation of a soluble form of APP (sAPPα), and (ii) the greater insights into underlying disease mechanisms.
amyloidogenic pathway, which results in the formation of
Aβ peptides that can form insoluble aggregates, a hallmark 2. Materials and methods
of AD. In the amyloidogenic pathway, APP is cleaved in 2.1. Study design
distinct positions by two secretases (β and γ), producing This study was designed to develop a 3D model of the adult
different sizes of Aβ (Aβ and Aβ ), where Aβ has SVZ-NSC microenvironment, representing a brain area,
40
42
42
more significant aggregation potential, resulting in senile aside from the hippocampus, that can be a target for early
plaques. Consequently, oxidative stress is observed during events of neurodegeneration in AD. Briefly, SVZ-derived
the formation of these plaques, inducing inflammatory NSCs were isolated from six-week-old C57BL/6 mice,
responses, which enhances the aggregation of Aβ peptides cultured as neurospheres, and bioprinted with or without
and impairs synaptic plasticity. Aβ 1–42 oligomers in the bioink composition. The constructs’
As the brain is distinctly dynamic, the complexity of physicochemical properties were characterized; the
NSCs and Aβ oligomer interactions demands investigating neurosphere areas were measured; and cell proliferation,
AD using novel strategic models. Biotechnology and oxidative stress, and cell differentiation were quantified.
bioengineering have much to contribute, especially 2.2. Reagents and equipment
providing tools to develop biomaterials that may increase All reagents and equipment used in this work are described
knowledge of pathophysiological mechanisms of the in Table 1.
disease, in addition to reducing the number of animals
used and highlighting specific pathways to be studied. 2.3. Preparation of the hydrogel
Recently, valuable attention has been directed toward 3D The hydrogel (the polymeric base of the bioink) was
models, 14–16 which create dynamic microenvironments composed of a homogenized combination of low-viscosity
that mimic the complexity of various tissues, including the sodium alginate (ALG; molecular weight [M ]: 30–100
W
brain. kDa) and gelatin (GEL; M : ~ 50–100 kDa; type A from
W
Volume 10 Issue 5 (2024) 503 doi: 10.36922/ijb.3751