International Journal of Molecular Medical Science, 2024, Vol.14, No.4, 252-263 http://medscipublisher.com/index.php/ijmms 254 2.3 Environmental and lifestyle interactions In addition to genetic mutations, environmental factors and lifestyle choices play a significant role in the progression of AD, particularly in individuals with a genetic predisposition. Gene-environment interactions are crucial in modulating the onset and severity of the disease. For example, carriers of the APOE ε4 allele are more susceptible to environmental risk factors such as poor diet, lack of physical activity, and exposure to toxins, which can exacerbate the pathogenic processes leading to AD (Lacour et al., 2019). Moreover, lifestyle interventions that target these modifiable risk factors, such as maintaining a healthy diet, regular exercise, and cognitive stimulation, have been shown to mitigate the effects of genetic risks. These findings highlight the potential for gene-environment interactions to be leveraged in preventive strategies aimed at reducing the incidence and delaying the onset of AD, particularly in genetically at-risk populations (Giau et al., 2019). 3 Mechanisms and Targets of Gene Therapy in AD 3.1 Amyloid-beta and tau pathways Gene therapy approaches targeting the amyloid-beta (Aβ) plaques and tau tangles, the two main pathological hallmarks of Alzheimer's disease (AD), have shown promise in mitigating disease progression. The accumulation of Aβ peptides, resulting from the cleavage of amyloid precursor protein (APP) by β- and γ-secretases, triggers a cascade leading to tau hyperphosphorylation and aggregation into neurofibrillary tangles (Roda et al., 2022). Gene therapy strategies focus on either reducing the production of Aβ or enhancing its clearance. For instance, targeting the BACE1 enzyme, which is involved in Aβ production, or using gene-editing tools like CRISPR/Cas9 to correct mutations in APP, PSEN1, and PSEN2 genes, has been explored to reduce amyloid plaque formation (Figure 2) (Sun et al., 2018). Additionally, tau-targeting therapies, such as using RNA interference or CRISPR/Cas9 to prevent tau hyperphosphorylation, are being developed to reduce neurofibrillary tangle formation and subsequent neuronal damage (Kent et al., 2020). Enhancing amyloid clearance is another critical strategy in gene therapy for AD. This can be achieved by upregulating genes involved in Aβ degradation or by modulating the immune system to enhance microglial activity, which is responsible for clearing amyloid plaques. Tau aggregation, which correlates more closely with cognitive decline than amyloid plaques, can be mitigated through gene therapies that stabilize microtubules or prevent tau from becoming hyperphosphorylated and forming tangles (Congdon and Sigurdsson, 2018). 3.2 Neuroprotective gene therapy Neuroprotective gene therapy focuses on enhancing the expression of proteins that protect neurons from the toxic effects of Aβ and tau. One promising approach involves the delivery of genes encoding neuroprotective factors like brain-derived neurotrophic factor (BDNF) or nerve growth factor (NGF). NGF, in particular, has been shown to reduce amyloidogenesis and promote neuronal survival by interacting with the TrkA receptor, which is crucial for neuronal function (Triaca et al., 2016). Gene therapies that increase NGF expression in the brain have demonstrated the ability to reduce tau phosphorylation and prevent neurodegeneration, suggesting a potential therapeutic strategy for AD (Zhou et al., 2020). 3.3 Gene editing and CRISPR/Cas9 The advent of CRISPR/Cas9 technology has opened new avenues for gene therapy in AD by enabling precise editing of genes associated with the disease (Li and Li, 2024). CRISPR/Cas9 can be used to correct pathogenic mutations in genes such as APP, PSEN1, and PSEN2, thereby reducing the production of toxic Aβ peptides (Adji et al., 2022). Furthermore, CRISPR/Cas9 can be employed to modulate gene expression or to insert genes that confer neuroprotection, making it a versatile tool for addressing the complex genetic factors involved in AD (Lu et al., 2021). However, the application of CRISPR/Cas9 in AD also raises significant ethical considerations and technical challenges. The potential for off-target effects, where unintended sections of DNA are edited, poses risks that need to be carefully managed. Moreover, the long-term implications of gene editing, particularly in the brain, are not
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