Direct Conversion of Fibroblast into Neurons for Alzheimer's Disease Research: A Systematic Review

Abstract

Background: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder without a cure. Innovative disease models, such as induced neurons (iNs), could enhance our understanding of AD mechanisms and accelerate treatment development. However, a review of AD human iN studies is necessary to consolidate knowledge.

Objective: The objective of this review is to examine the current body of literature on AD human iN cells and provide an overview of the findings to date.

Methods: We searched two databases for relevant studies published between 2010 and 2023, identifying nine studies meeting our criteria.

Results: Reviewed studies indicate the feasibility of generating iNs directly from AD patients' fibroblasts using chemical induction or viral vectors. These cells express mature neuronal markers, including MAP-2, NeuN, synapsin, and tau. However, most studies were limited in sample size and primarily focused on autosomal dominant familial AD (FAD) rather than the more common sporadic forms of AD. Several studies indicated that iNs derived from FAD fibroblasts exhibited abnormal amyloid-β metabolism, a characteristic feature of AD in humans. Additionally, elevated levels of hyperphosphorylated tau, another hallmark of AD, were reported in some studies.

Conclusion: Although only a limited number of small-scale studies are currently available, AD patient-derived iNs hold promise as a valuable model for investigating AD pathogenesis. Future research should aim to conduct larger studies, particularly focusing on sporadic AD cases, to enhance the clinical relevance of the findings for the broader AD patient population. Moreover, these cells can be utilized in screening potential novel treatments for AD.

Keywords: APOE; APP; Adult human dermal fibroblasts; Alzheimer’s disease; amyloid-β; familial Alzheimer’s disease; human induced-neurons; sporadic Alzheimer’s disease; tau.

Fig. 1

Comparison between direct neuronal conversion and indirect reprogramming. Comparison of direct and indirect reprogramming to the neuronal cell-fate. Somatic cells from patients can be directly or indirectly reprogrammed to iNs. Direct reprogramming can be achieved by overexpression of transcription factors (such as Brn2, Ascl1, and Myt1) or other supplemental neurogenesis factors, which reprogram fibroblast cells under 30 days. In contrast, somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) with Yamanaka transcription factors [101]. Such methods lengthen the reprogramming timeline as quality control assays for karyotypic stability and pluripotency must be conducted. Advantages and limitations of each method are summarized in the figure.

Fig. 2

Screening Flow Diagram. For records identification in PubMed the following search criteria were used: (“alzheimer’s”[Title/Abstract] OR “alzheimer”) AND (((“induced neurons”[Title/Abstract]) OR “induced neuronal cell” OR “induced neuron” OR (“reprogrammed”[Title/Abstract]))). For records identification in Web of Science the following search criteria were used: #1 AND #2 AND #3 AND #4. Where #1 ((TI = (alzheimer’s)) OR AB = (alzheimer’s)), #2 ((TI = (alzheimer)) OR AB = (alzheimer)), #3 (((((TI = (induced neurons)) OR TI = (induced neurons))) OR TI = (induced neuronal cell)) OR TI = (induced neuron)) OR TI = (reprogrammed), #4(((((AB = (induced neurons)) OR AB = (induced neurons))) OR AB = (induced neuronal cell)) OR AB = (induced neuron)) OR AB = (reprogrammed). Inclusion and exclusion criteria are presented in the main text.