Abstract
Despite a wealth of knowledge gained in the past three decades concerning the molecular underpinnings of Alzheimer’s disease (AD), progress towards obtaining effective, disease modifying therapies has proven to be challenging. In this manner, numerous clinical trials targeting the production, aggregation, and toxicity of beta-amyloid, have failed to meet efficacy standards. This puts into question the beta-amyloid hypothesis and suggests that additional treatment strategies should be explored. The recent emergence of CRISPR/Cas9 gene editing as a relatively straightforward, inexpensive, and precise system has led to an increased interest of applying this technique in AD. CRISPR/Cas9 gene editing can be used as a direct treatment approach or to help establish better animal models that more faithfully mimic human neurodegenerative diseases. In this manner, this technique has already shown promise in other neurological disorders, such as Huntington’s disease. The purpose of this review is to examine the potential utility of CRISPR/Cas9 as a treatment option for AD by targeting specific genes including those that cause early-onset AD, as well as those that are significant risk factors for late-onset AD such as the apolipoprotein E4 (APOE4) gene.
Highlights
Despite a wealth of knowledge gained in the past three decades concerning the molecular underpinnings of Alzheimer’s disease (AD), progress towards obtaining effective, disease modifying therapies has proven to be challenging
The classic neuropathological footprints of Alzheimer’s Disease (AD) are characterized by extracellular senile plaques composed of beta-amyloid and intracellular lesions of truncated and hyperphosphorylated tau leading to neurofibrillary tangles (NFTs) [5]
Imaging studies in autosomal dominant AD brains have documented early accumulation of beta-amyloid on PET scans as early as 15–20 years before symptoms became evident [9,10], suggesting there is, potentially, a large therapeutic window to intercede. These studies have reinforced the rationale behind the beta-amyloid hypothesis, which suggests that beta-amyloid in the form of toxic oligomers is thought to be the key initiating species leading to all downstream events culminating in synapse loss, neurodegeneration and dementia [11,12,13,14]
Summary
The RNA-guided clustered regularly interspaced short palindromic repeats/CRISPR associated nuclease 9 (CRISPR/Cas9) system is a revolutionary genome editing tool derived from the bacterial Type II CRISPR adaptive immune system [18,19]. The authors sought to disrupt this mutation in vivo using Tg2576 mice, which carry multiple copies of the APP Swedish mutation To accomplish this, they injected DNA encoding both Cas and guide RNAs in AAV vectors into the hippocampus of transgenic mice. They injected DNA encoding both Cas and guide RNAs in AAV vectors into the hippocampus of transgenic mice It remains to be seen if such manipulation will decrease the pathology and behavior deficits associated with Tg2576 mice, the authors were able to show some disruption of the APP Swedish gene, mostly in the form of single base pair insertions. Tantalizing in its promise, a more systematic analysis of the targeted cells in the hippocampus needs to be undertaken to understand the low editing efficiency in vivo
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