Amyloid Cascade Hypothesis for the Treatment of Alzheimer’s Disease: Progress and Challenges

Wu, Tong; Ding, Lin; Cheng, Yong; Jiang, Senze; Riaz, Muhammad Waheed; Fu, Nina; Mou, Chenhao; Ye, Menglu; Zheng, Ying

doi:10.14336/ad.2022.0412

Cited by 29 publications

(21 citation statements)

References 111 publications

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“…Both sigma receptors are involved with lipid homeostasis, and inhibition of sigma-2 receptors can bind neurons and may reduce cognitive dysfunction associated with Alzheimer’s disease [ 75 ]. Sigma-2 antagonists in particular appear to halt the amyloid cascade associated with Alzheimer’s disease in which beta-amyloids accumulate in the brain [ 76 , 77 ].…”

Section: Reviewmentioning

confidence: 99%

The Sigma Enigma: A Narrative Review of Sigma Receptors

Pergolizzi¹,

Varrassi²,

Coleman³

et al. 2023

Cureus

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The sigma-1 and sigma-2 receptors were first discovered in the 1960s and were thought to be a form of opioid receptors initially. Over time, more was gradually learned about these receptors, which are actually protein chaperones, and many of their unique or unusual properties can contribute to a range of important new therapeutic applications. These sigma receptors translocate in the body and regulate calcium homeostasis and mitochondrial bioenergetics and they also have neuroprotective effects. The ligands to which these sigma receptors respond are several and dissimilar, including neurosteroids, neuroleptics, and cocaine. There is controversy as to their endogenous ligands. Sigma receptors are also involved in the complex processes of cholesterol homeostasis and protein folding. While previous work on this topic has been limited, research has been conducted in multiple disease states, such as addiction, aging. Alzheimer's disease, cancer, psychiatric disorders, pain and neuropathic pain, Parkinson's disease, and others. There is currently increasing interest in sigma-1 and sigma-2 receptors as they provide potential therapeutic targets for many disease indications.

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Section: Reviewmentioning

confidence: 99%

The Sigma Enigma: A Narrative Review of Sigma Receptors

Pergolizzi¹,

Varrassi²,

Coleman³

et al. 2023

Cureus

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“…Aβ is hypothesized to play an important role in AD. , However, the amyloid hypothesis has not been able to achieve universal consensus over the years. The lack of a clear understanding of amyloid-triggered pathways has widened the gap in research, creating a need for further investigation assuming the Aβ hypothesis . Moreover, recent drugs’ success based on Aβ hypothesis, such as Lecanemab, a humanized IgG1 monoclonal antibody, which is approved by FDA to treat AD patients, has increased the faith in the amyloid hypothesis .…”

Section: Introductionmentioning

confidence: 99%

“…The lack of a clear understanding of amyloid-triggered pathways has widened the gap in research, creating a need for further investigation assuming the Aβ hypothesis. 7 Moreover, recent drugs' success based on Aβ hypothesis, such as Lecanemab, 8 a humanized IgG1 monoclonal antibody, which is approved by FDA to treat AD patients, has increased the faith in the amyloid hypothesis. 9 Therefore, strategies targeting Aβ may help in suppressing disease progression.…”

Section: Introductionmentioning

confidence: 99%

Modeling Inhibitory Effects of Chlorogenic Acid on Amyloid Beta Aggregation

Majid,

Garg

2024

Ind. Eng. Chem. Res.

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Amyloid β (Aβ) aggregation is considered one of the major factors in Alzheimer's disease (AD) pathogenesis. Seeking therapeutic molecules that could inhibit the aggregation effectively has been a major research focus in recent years. Chlorogenic acid (CGA) is reported to have an inhibition effect on Aβ aggregation, and its effectiveness is reported to be enhanced when loaded with selenium nanoparticles. Herein, a previously reported kinetic model based on radical polymerization studying only Aβ aggregation is modified. The modified model is used to study the inhibitory effects of CGA and CGA loaded on nanoparticles on Aβ aggregation. Parameter tuning is done with the experimental data to estimate the values of new parameters introduced in the modified model. The simulated results from the modified model are in good agreement with the experimental data at different doses of both CGA and CGA loaded on the nanoparticles. Moreover, the sensitivity analyses demonstrate the robustness of the model. It is hypothesized that the modified model may help elucidate the Aβ-drug interactions revealing therapeutic insights and may also be used to study the inhibitory effects of other drugs, such as polyphenols, metal chelators, peptides, and nanoparticles that show a similar inhibition trend for the inhibition of Aβ fibrillation.

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“…Over the years, several hypotheses have been formulated to explain how the neuropathological features of AD are causally related to each other, underpinning its pathogenesis. Among these, the most debated in scientific communities is the “amyloid cascade hypothesis” which posed that the progressive accumulation of Aβ in the brain triggers a complex cascade of events that result in the tau hyperphosphorylation, loss of synapses, glial activations, progressive deficiency of neurotransmitters, and neural death [ 19 , 20 ]. However, this hypothesis has been subject to several criticisms or alternative interpretation because of lack of a strong link that can explain how Aβ can cause all these neuropathological phenotypes [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

The Nerve Growth Factor Receptor (NGFR/p75NTR): A Major Player in Alzheimer’s Disease

Bruno

Abondio

Montesanto

et al. 2023

IJMS

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Alzheimer’s disease (AD) represents the most prevalent type of dementia in elderly people, primarily characterized by brain accumulation of beta-amyloid (Aβ) peptides, derived from Amyloid Precursor Protein (APP), in the extracellular space (amyloid plaques) and intracellular deposits of the hyperphosphorylated form of the protein tau (p-tau; tangles or neurofibrillary aggregates). The Nerve growth factor receptor (NGFR/p75NTR) represents a low-affinity receptor for all known mammalians neurotrophins (i.e., proNGF, NGF, BDNF, NT-3 e NT-4/5) and it is involved in pathways that determine both survival and death of neurons. Interestingly, also Aβ peptides can blind to NGFR/p75NTR making it the “ideal” candidate in mediating Aβ-induced neuropathology. In addition to pathogenesis and neuropathology, several data indicated that NGFR/p75NTR could play a key role in AD also from a genetic perspective. Other studies suggested that NGFR/p75NTR could represent a good diagnostic tool, as well as a promising therapeutic target for AD. Here, we comprehensively summarize and review the current experimental evidence on this topic.

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Amyloid Cascade Hypothesis for the Treatment of Alzheimer’s Disease: Progress and Challenges

Cited by 29 publications

References 111 publications

The Sigma Enigma: A Narrative Review of Sigma Receptors

The Sigma Enigma: A Narrative Review of Sigma Receptors

Modeling Inhibitory Effects of Chlorogenic Acid on Amyloid Beta Aggregation

The Nerve Growth Factor Receptor (NGFR/p75NTR): A Major Player in Alzheimer’s Disease

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