Alzheimer’s Disease: From Molecular Mechanisms to Therapeutic Opportunities

Dear Colleagues,

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease among elderly persons. It is a complex neurodegenerative disorder characterized by the progressive loss of neurons. This typically leads to severe impairments in cognitive functions, including memory and learning. The key pathological features of AD include the deposition of highly insoluble amyloid β peptides and the formation of neurofibrillary tangles (NFTs) in the brain. 

There is cumulating evidence that a sustained glial-mediated inflammation is a major contributor of the neurodegenerative processes and cognitive deficits observed in AD.

Recent findings clearly show that epigenetic mechanisms are dysregulated even at the early stage of AD progression. 

Amyloid-β (Aβ) fragments as well as hyperphosphorylation of Tau are hallmarks of AD, and these are found in extracellular plaques and intracellular fibrils in the brain of individuals with AD. Some researchers have demonstrated plaques and tangles as apparently primary lesions. Moreover, experimental data suggest that these two lesions are intimately related. However, whether it is the oligomeric or the soluble species of Aβ and Tau that mediate toxicity is still unclear. Some molecular mechanisms linking tau and Aβ toxicities have been proposed linking oxidative stress, Aβ turnover, the contribution of thiol groups, and the role of mitochondrial activities in the AD pathogenesis. Tau proteins impact on mitochondrial energy metabolism, inflammation, as well as a number of housekeeping processes, including protein degradation through the Ubiquitin–Proteasome System (UPS) and autophagy.

The molecular mechanisms responsible for the initiation and development of both familial and sporadic AD are thus still poorly understood despite intense efforts. There is still no treatment to prevent or cure this disease. However, the Icelandic mutation (APP A673T) has been shown to reduce the formation of beta-amyloid peptides and prevent the development of AD even in persons who are more than 95 years old. This Icelandic mutation also reduces the formation of Aβ even in the presence of some familial AD mutation. This is a clue to a potential preventive treatment.

Many powerful techniques, including genome and exome sequencing, now permit exploring the molecular mechanisms of this disease. CRISPR-derived genome editing technologies even permit intervention, which could prevent or at least slow down the progression of the disease by correcting the mutation responsible for familial forms of AD or by introducing the protective Icelandic mutation.

This Special Issue of Cells will thus review recent research on the amyloid hypothesis. This will include beta-amyloid-induced dysfunction of neuronal synapses due to changes in synaptic proteins and neurotransmitter and potential interventions with CRISPR-derived gene editing technologies.

Prof. Dr. Jacques P. Tremblay
Guest Editor

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• Alzheimer’s
• molecular mechanism
• genome editing
• CRISPR gene editing