Speeding up Alzheimer's research: Progerin turbocharges cellular models for quicker drug screening

By Dr. Priyom Bose, Ph.D.Reviewed by Benedette Cuffari, M.Sc.Oct 31 2023

The pathogenesis of Alzheimer’s Disease (AD), a leading cause of dementia, remains unclear. One notable limitation of current cellular models is that they lack an aging in vitro environment.

Progerin is a truncated protein that causes Hutchinson-Gilford Progeria Syndrome (HGPS), a disease that causes individuals to age prematurely. Prior research has reported similarities between AD and HGPS cells.

A recent Scientific Reports study discusses the impact of progerin expression on neural progenitor cells that exhibit familial AD (FAD) mutations. 

Study: Development of an accelerated cellular model for early changes in Alzheimer’s disease. Image Credit: unoL / Shutterstock.com

Background

The nuclear lamina comprises A-type lamins (A and C) and B-type lamins (B1 and B2). A-type lamins are products of the LMNA gene, whereas B-type lamins are encoded by LMNB13 and LMNB24.

The presence of progerin in the nucleus leads to lamin B1 downregulation, distorted nuclear morphology, and eventual apoptosis. This is similar to phenotypes observed in the AD model.

AD can categorized as FAD, which begins before an individual turns 65, or sporadic AD (SAD), which generally occurs after the age of 65 years. Neurofibrillary tangles (NFTs) comprising tau protein and senile plaques consisting of β-amyloid (Aβ) are features of AD.

Concerning plaque formation, aging is a key driver; however, the exact mechanisms responsible for these protein aggregations have not been conclusively researched. Nevertheless, some studies have indicated a potential role of nuclear lamina in AD. 

About the study

The current study altered a well-known cellular model for AD to determine whether progerin expression could accelerate the development of AD phenotypes.

To this end, human neural progenitor cells (hNPC) were extracted from the ventral mesencephalon region of human fetal brains. For lentivirus packaging and transduction, HEK293T cells were co-transfected with two virus packaging vectors and lentiviral plasmids.

Subsequently, total genomic RNA was extracted, and a quantitative polymerase chain reaction (PCR) assay was performed. To assess the mean telomere length, DNA samples from ReN cells were extracted. Various assays were conducted to study cell cycle, cell death, and oxidative stress. 

Key findings

The overexpression of lamin A was observed in ReN cells, which led to higher oxidative stress, reactivation of the cell cycle, and cell death; however, progerin augmented these phenotypes. These findings reflect the potential role of lamin A in AD pathology.

These observations imply that the expression of progerin or lamin A could lead to aging, thereby increasing the risk of disease development. More specifically, progerin expression accelerated the development of AD phenotypes to three to four weeks from eight to 16 weeks. 

With the combination of FAD mutations and ectopic progerin expression, Aβ accumulations, cell death, and higher tau phosphorylation were observed. Distinct alterations in the cell cycle may not be possible by the four-week expression of FAD mutations because AD manifests late. This motivates the use of progerin to limit AD progression. 

In most circumstances, cells that contain only FAD mutations do not exhibit aging. These cells can eliminate toxic proteins because their cellular mechanics are unchanged; however, progerin leads to senescence in cells, which disrupts the balance of the nucleoskeleton.

This is crucial because, for neighboring cells, it offers an aged microenvironment. Thus, neighboring cells become more vulnerable and may eventually die.

Progerin leads to the secretion of senescent-associated secretory factors (SAPSs), which influence neighboring cells and contribute to the creation of an aged cell culture environment. Therefore, the introduction of progerin acts in both cells non-autonomously and autonomously, which accelerates neurodegeneration by inducing aging.

The current model was built on the three-dimensional (3D) AD cellular model and was more efficient than time-consuming animal models. This model was also associated with a more rapid manifestation of both fibril formation and higher tau phosphorylation.

In addition to 3D cultures, this system can also be used in 2D cultures, which may be a more viable platform for studying AD mechanisms and drug screening. Future research should consider different groups and compare their proteomic and transcriptomic profiles, which would assist in analyzing novel pathways in AD pathology and detect early biomarkers of the disease.

Conclusions

The current study demonstrated a connection between lamin A and AD pathology. By inducing progerin expression in FAD-mutant cells, an aged environment could be created and subsequently generate strong characteristics of AD within a short period. A notable benefit of the current approach is that progerin-induced aging can be used to model other diseases with late-onset.