About this Research Topic

Background

Alzheimer’s (AD) is a degenerative brain disease and the most common cause of dementia. Multiple hypotheses about the underlying pathophysiology of AD have been proposed, including those focused on pathogenic deposition of amyloid beta (Aβ) or hyperphosphorylated microtubule associated protein TAU (MAPT) aggregation, inflammation, dysfunctional cholinergic neurotransmission, oxidative stress, excessive deposition of metal ions (zinc, copper or iron), mutations in predisposing disease susceptibility genes, abnormal calcium (Ca2+) signalling, and mitochondrial dysfunction. The Aβ plaque and Tauopathy hypotheses have been the mainstream concept underlying AD research for decades. However, the failure of almost all previous AD drug trials, including those targeting Aβ or MAPT aggregates, have raised doubts about the pathogenicity of the current therapeutic targets. There is an urgent need to find new drug targets based on a better understanding of the link between different etiological factors of the disease, particularly those overlooked previously.

Keeping in mind the deficits in our understanding of the AD pathogenesis, the goal of this special issue is to showcase novel as well as classical mechanisms underlying the cellular and molecular pathologies of AD, highlighting research providing novel mechanistic links between proposed etiological factors, to fill gaps in our current understanding of AD pathogenesis. For example, hyperphosphorylation and cross-linking of MAPT monomers underlies the formation of insoluble MAPT aggregates commonly known as neurofibrillary tangles (NFTs). NFTs have been identified as an underlying factor disrupting neuroaxonal transport leading to cellular death. A large body of evidence suggests that MAPT hyperphosphorylation results from perturbations of cellular signalling, mainly through imbalance of the activities of different protein kinases and phosphatases. On the other hand, it has been suggested that transglutaminase (TGM) catalyses the cross-linking of hyperphosphorylated MAPT monomers causing the formation of NFTs. The link between TGM and MAPT hyperphosphorylation is not well established. Moreover, it is not clear if TGM selectively crosslinks hyperphosphorylated MAPT, or other proteins as well. It is surprising therefore that anti-MAPT antibodies have been promoted by pharmaceutical companies for the treatment of tauopathy in AD without first addressing these fundamental mechanisms. Thus far, the failure of anti-hyperphosphorylated TAU immunotherapies highlights major gaps in our understanding of certain critical aspects of the disease biology, limiting the success of such therapeutic approaches. Inhibitors targeting TGM or the protein kinases that hyperphosphorylated MAPT may be a more successful therapeutic approach compared to anti-TAU therapies. This issue will focus on research articles that scrutinize existing theories of AD to provide new insights.

This research topic encourages submissions that shed light on different aspects of the cellular and molecular pathologies leading to the progression of AD. The focus is on submissions linking, reinterpreting, or critically revisiting existing hypotheses of the diseases as mentioned below:
- Amyloid beta.
- TAU and other cytoskeletal protein abnormalities
- Inflammation
- Metal ion deposition in AD brain, specifically Iron
- Abnormal Calcium ion signaling
- Molecular and ultrastructural deficits in mitochondria.
- Novel blood or cerebrospinal fluid-based biomarkers of AD, and their underlying mechanisms within the disease pathogenesis.

We accept different article types including Mini-Reviews, Brief Research Reports and Perspectives. A full list of accepted article types, including descriptions, can be found at this link. Comprehensive studies are highly encouraged.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Data Report
• Editorial
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• ... View all formats

Articles that are accepted for publication by our external editors following rigorous peer review incur a publishing fee charged to Authors, institutions, or funders.

Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Data Report
• Editorial
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Technology and Code

Keywords: alzheimer's disease, muscarinic signaling, mitochondria

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