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Pathophysiology of Alzheimer’s disease
Published in Howard H. Feldman, Atlas of Alzheimer's Disease, 2007
Najeeb Qadi, Sina Alipour, B. Lynn Beattie
APP isoforms range in length from 695 to 770 amino acids and are present through the membranes of a variety of organs within the human body. While the overall physiologic function of APP has not yet been determined definitely, it can serve as a cell surface receptor, as a heparin binding site, as a precursor to a growth-factor-like agent, and as a regulator of neuronal copper homeostasis.13,14 Mice with APP knockout are 15–20% underweight compared with age-matched controls, exhibit behavioral abnormalities, and exhibit neuronal dysfunction with significant reactive astrocytosis and gliosis.15 Whereas mice with knockout of APP and amyloid precursor-like proteins, termed APLP1 and APLP2, survive through embryonic development, but die shortly after birth. About 81% of triple mutants show cranial abnormalities and 68% triple mutants (APP, APLP1, APLP2?) have cortical dysplasia, a phenotype that resembles human type II lissencephaly.16
The contribution of C. elegans neurogenetics to understanding neurodegenerative diseases
Published in Journal of Neurogenetics, 2020
Joseph J. H. Liang, Issa A. McKinnon, Catharine H. Rankin
A dominant, but recently challenged hypothesis for the cause of AD is the Aβ hypothesis (Hardy & Higgins, 1992; Karran & De Strooper, 2016; Selkoe & Hardy, 2016). In mammals, APP is part of a family of proteins that also includes APLP1 and APLP2: all three proteins have a large extracellular region containing conserved E1 and E2 domains, a single transmembrane domain and a small cytosolic domain (Kang et al., 1987). This family of proteins is required for viability and brain development – they have essential and redundant Aβ-independent functions during development. Notably, out of the three proteins, only APP contains the Aβ domain. While the normal function of Aβ is not well understood, it has been shown that the cleaved protein is involved in a variety of cellular activities including activating kinase enzymes (Tabaton, Zhu, Perry, Smith, & Giliberto, 2010), protecting against oxidative stress (Zou, Gong, Yanagisawa, & Michikawa, 2002), functioning as a transcription factor (Maloney & Lahiri, 2011) and having a pro-inflammatory activity (Figure 1; Kagan et al., 2012).
Homozygous familial hypercholesterolemia and its treatment by inclisiran
Published in Expert Opinion on Orphan Drugs, 2020
A David Marais, Dirk J Blom, Frederick J Raal
The gene for PCSK9 is located on chromosome 1p32.3. The protein is very strongly expressed in the liver, but other organs and cells may also express it. Although splice variants of PCSK9 are recognized [22], the chief and only secreted product is a 63kda protein that is catalytically inactive as explained above. Translation of the RNA yields a protein comprising a signal peptide (amino acids 1–30), a prodomain (amino acids 31–152), a catalytic domain (amino acids 153–452), and a C-terminal domain (amino acids 425–692). The prodomain may promote binding to LDL and PCSK9 can thus be detected on LDL. The catalytic domain performs the auto-catalysis resulting in the cleavage at residue 152. This same region binds the epidermal growth precursor homologous binding domain A of the LDL receptor. Some modulation of this interaction between PCSK9 and the LDL receptor involves the prodomain of PCSK9. Potentiation of LDL receptor degradation comes from the C-terminus of PCSK9. This part of the molecule can also bind amyloid precursor-like protein 2 (APLP2) which is expressed on the hepatocyte. It is possible that PCSK9, apart from binding the apoB-binding receptors, also binds other receptors. Sortilin-1, a transmembrane protein that has been associated with hypercholesterolemia, has a high affinity for PCSK9 and may be involved in returning PCSK9 for re-secretion [23].
Caspase inhibitors: a review of recently patented compounds (2013-2015)
Published in Expert Opinion on Therapeutic Patents, 2018
Hyemin Lee, Eun Ah Shin, Jae Hee Lee, Deoksoo Ahn, Chang Geun Kim, Ju-Ha Kim, Sung-Hoon Kim
Xu et al. [103] invented synthetic 2-acetic acid derivatives as caspase-3 inhibitors for the prevention and treatment of pathological conditions associated with caspase-dependent cell death. Here, to improve membrane permeability, 2-acetic acid derivatives (Figure 4(a,b)) were synthesized for the prevention and treatment of acquired immune deficiency syndrome, severe forms of hepatitis, spinal cerebellar disorders, cerebral ischemia, muscular dystrophy, osteoarthritis, AD, PD, HD, ALS, and brain damage [103]. Among several compounds that inhibit protease activity, the IC50 values of SUN-6 (Figure 5(a)), SUN-9 (Figure 5(b)), SUN-19 (Figure 5(c)), and SUN-21 (Figure 5(d)) against caspase-3 were 36.40 ± 1.06 µM, 42.48 ± 3.26 µM, 76.43 ± 2.06 µM, and 83.25 ± 4.22 µM, respectively. SUN-6 was the most effective. β-amyloid precursor protein (APP) and two APP-like proteins (APLP1 and APLP2) are cleaved by caspases at the C-terminus in the brains of patients with AD [104]. However, although these compounds were claimed to be effective in treating several neurodegenerative diseases by virtue of their caspase inhibitory effects, the efficacy and toxicity of these compounds should be comparatively examined in vitro and in vivo in clinical trials in patients with AD compared to classic anti-AD agents along with safety, ADME, and pharmacokinetic studies.