β-Secretase (BACE1) Inhibitors From Natural Products
Atanu Bhattacharjee, Akula Ramakrishna, Magisetty Obulesu in Phytomedicine and Alzheimer’s Disease, 2020
Formation of extracellular amyloid beta (Aβ) plaques, with drastic neuronal and synaptic reductions in the cholinergic system of the brain, is considered to be the major pathological hallmark of AD (Azimi et al., 2017; Berrino, 2002). According to the ‘beta-amyloid cascade’, deposition of the Aβ peptide triggers neuroinflammation, resulting in neurodegeneration. Aβ is derived from sequential proteolytic cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretases. Initial cleavage by beta-secretase (beta-site of APP cleaving enzyme; BACE1), a membrane-anchored aspartic protease, generates a soluble N-terminal fragment and a membrane-associated C-terminal fragment. The C-terminal fragment then undergoes proteolysis by gamma-secretase to give the Aβ peptide (Skovronsky et al., 2006; Brinton et al., 1998). BACE1 has been proposed to be a promising therapeutic target as it initiates the first step in Aβ production (Barao et al., 2016). Neuroinflammation of AD likely starts as a host defense response to the damaging effects of the amyloid deposits in the brain. Hence, anti-inflammatory drugs could be another potential therapeutic target to delay progress of AD (Zhang et al., 2015).
Many Applications of Hemp in Neurological & Gut-Brain Axis *
Betty Wedman-St Louis in Cannabis as Medicine, 2019
The involvement of CB2 receptors in Alzheimer’s disease was demonstrated in a number of human studies. Inspections of post-mortem brains from individuals with Alzheimer’s disease showed that CB2 receptors are upregulated in cells that are linked to amyloid beta (Aβ)-enriched neuritic plaques.7–10 The deposition of amyloid beta plaques in the brain is involved in Alzheimer’s disease pathology. Other researchers found markedly higher CB2 receptor levels in individuals with severe Alzheimer’s disease compared with age-matched controls or people with moderate Alzheimer’s.11 Activation of the CB2 receptor has resulted in beneficial effects in Alzheimer’s disease, including the inhibition of microglial activation in mice.12
The nervous system
Laurie K. McCorry, Martin M. Zdanowicz, Cynthia Y. Gonnella in Essentials of Human Physiology and Pathophysiology for Pharmacy and Allied Health, 2019
Although the exact cause of Alzheimer’s disease is still uncertain, great strides have been made in recent years to enhance our understanding of the disease process. Two pathologic “hallmarks” found in the brains of patients with Alzheimer’s disease are the presence of beta amyloid plaques, and neurofibrillary tangles. Beta amyloid plaques form from accumulations of a brain protein called amyloid beta. This protein is derived from a larger protein called amyloid precursor protein (APP). There is evidence that improper cleavage or “proteolysis” of the APP leads to the formation of amyloid beta proteins that subsequently accumulate in CNS neurons and alters their function. Neurofibrillary tangles are twisted accumulations of a protein called tau that form in the cytoplasm of affected neurons. Because the cytoplasm is essential for the transport of nutrients and other essential substances in the neuron, the presence of neurofibrillary tangles may interfere with this and damage the neuron.
Viruses - a major cause of amyloid deposition in the brain
Published in Expert Review of Neurotherapeutics, 2023
Tamas Fulop, Charles Ramassamy, Simon Lévesque, Eric H Frost, Benoit Laurent, Guy Lacombe, Abedelouahed Khalil, Anis Larbi, Katsuiku Hirokawa, Mathieu Desroches, Serafim Rodrigues, Karine Bourgade, Alan A Cohen, Jacek M. Witkowski
First, we should consider how the amyloid beta is produced. There are two pathways to process the membrane-bound amyloid precursor protein (APP). The first is non-amyloidogenic meaning that the external part of the APP is cleaved in a sequential manner by the α-secretase followed by the γ-secretase. The second is the amyloidogenic pathway which starts with the internalization of the APP in endosomes where they are cleaved by the β-secretase followed by the γ-secretase processing [7]. This gives rise to various amyloidogenic peptides, mainly to those of Aβ1–40 and the Aβ1–42 secreted in the extracellular space mostly linked to exosomes [36]. Researchers observing the failure of the treatment of AD which targets the amyloid beta were thinking that it should have some important reason for its production even if the clinical AD will never develop.
Focusing on oligomeric tau as a therapeutic target in Alzheimer’s disease and other tauopathies
Published in Expert Opinion on Therapeutic Targets, 2023
Moving forward, the key steps are to identify pathogenic, as opposed to merely pathological, form(s) of tau, and then rigorously assess their potential as drug targets. Coincidentally, an important lesson can be applied from recent efforts to develop immunotherapies against amyloid beta in AD. In particular, Lecanemab is selective for toxic forms of amyloid beta, and has produced statistically meaningful signals in clinical trials [86–88]. By comparison, clinical trials for earlier generation immunotherapies that indiscriminately target amyloid beta species have been spectacularly unsuccessful. Likewise, a growing body of evidence points to oligomeric tau as a major pathogenic species, distinct from other tau conformations, and one that deserves further attention as a therapeutic target. Simply stated, not all forms of tau (or amyloid beta) are bad. Drug development efforts should focus on structural configurations that may actively drive pathology.
Exposure to pyrethroids induces behavioral impairments, neurofibrillary tangles and tau pathology in Alzheimer’s type neurodegeneration in adult Wistar rats
Published in Drug and Chemical Toxicology, 2022
K. A. Iteire, A. T. Sowole, B. Ogunlade
Amyloid beta (Aβ or A-beta) denotes peptides of 36 – 43 amino acids that have been observed to be crucially involved in AD prognosis and as the major component of amyloid plaques found in the brains of Alzheimer patients (Hamley 2012). In AD and family of other related neurodegenerative diseases, called tauopathies, tau protein is abnormally hyperphosphorylated and aggregated into bundles of filaments (Grundke-Iqbal et al.1986). Tau pathology presents as intraneuronal neurofibrillary tangles of Paired Helical Filaments (PHF) sometimes admixed with Straight Filaments (SF) in AD brain. Aggregations of abnormally hyperphosphorylated filaments are also observed in dystrophic neuritis surrounding the β-amyloid plaque core and in the neuropilas neuropil threads (Braak et al.1986). Neurofibrillary degeneration of abnormally hyperphosphorylated tau is apparently required for the clinical diagnosis of AD and related tauopathies which can be studied by using immunohistochemical methods (Tomlinson et al.1970, Alafuzoff et al.1987, Arriagada et al.1992).
Related Knowledge Centers
- Peptide
- Amino Acid
- Amyloid Plaques
- Alzheimer's Disease
- Amyloid-Beta Precursor Protein
- Beta-Secretase 1
- Gamma Secretase
- Substrate Presentation
- Oligomer
- Prion