Efficacy and Safety of Ketone Supplementation or Ketogenic Diets for Alzheimer's Disease: A Mini Review

Alzheimer's disease (AD) is the most frequent age-related neurodegenerative disorder, with no curative treatment available so far. Alongside the brain deposition of β-amyloid peptide and hyperphosphorylated tau, neuroinflammation triggered by the innate immune response in the central nervous system, plays a central role in the pathogenesis of AD. Glucose usually represents the main fuel for the brain. Glucose metabolism has been related to neuroinflammation, but also with AD lesions. Hyperglycemia promotes oxidative stress and neurodegeneration. Insulinoresistance (e.g., in type 2 diabetes) or low IGF-1 levels are associated with increased β-amyloid production. However, in the absence of glucose, the brain may use another fuel: ketone bodies (KB) produced by oxidation of fatty acids. Over the last decade, ketogenic interventions i.e., ketogenic diets (KD) with very low carbohydrate intake or ketogenic supplementation (KS) based on medium-chain triglycerides (MCT) consumption, have been studied in AD animal models, as well as in AD patients. These interventional studies reported interesting clinical improvements in animals and decrease in neuroinflammation, β-amyloid and tau accumulation. In clinical studies, KS and KD were associated with better cognition, but also improved brain metabolism and AD biomarkers. This review summarizes the available evidence regarding KS/KD as therapeutic options for individuals with AD. We also discuss the current issues and potential adverse effects associated with these nutritional interventions. Finally, we propose an overview of ongoing and future registered trials in this promising field.

Helicobacter Pylori Urease: Potential Contributions to Alzheimer’s Disease

Alzheimer’s disease (AD) causes dementia and memory loss in the elderly. Deposits of beta-amyloid peptide and hyperphosphorylated tau protein are present in AD’s brain. A filtrate of Helicobacter pylori’s culture was previously found to induce hyperphosphorylation of tau in vivo, suggesting that bacterial exotoxins could permeate the blood brain barrier and directly induce tau’s phosphorylation. H. pylori, which infects ~60% of the world population and causes gastritis and gastric cancer, produces a pro-inflammatory urease (HPU). Here the neurotoxic potential of HPU was investigated in cultured cells and in rats. SH-SY5Y neuroblastoma cells exposed HPU (50-300 nM) produced reactive oxygen species (ROS) and had an increased [Ca2+]i. HPU-treated BV-2 microglial cells produced ROS, cytokines IL-1β and TNF-α, expressed Iba1 and showed reduced viability, consistent with a neurotoxic effect of HPU. Rats received daily i.p. HPU (5 µg) for 7 days. Hyperphosphorylation of tau at Thr205, Ser199 and Ser396 sites was seen in hippocampal homogenates of treated rats, with no alterations in total tau or GSK-3b levels. HPU was not detected in the brain homogenates. Behavioral tests were performed to assess cognitive impairments. Our findings support previous data suggesting an association between infection by H. pylori and tauopathies such as AD, possibly mediated by its urease.

High-Efficiency Expression and Purification of DNAJB6b Based on the pH-Modulation of Solubility and Denaturant-Modulation of Size

The chaperone DNAJB6b delays amyloid formation by suppressing the nucleation of amyloid fibrils and increases the solubility of amyloid-prone proteins. These dual effects on kinetics and equilibrium are related to the unusually high chemical potential of DNAJB6b in solution. As a consequence, the chaperone alone forms highly polydisperse oligomers, whereas in a mixture with an amyloid-forming protein or peptide it may form co-aggregates to gain a reduced chemical potential, thus enabling the amyloid peptide to increase its chemical potential leading to enhanced solubility of the peptide. Understanding such action at the level of molecular driving forces and detailed structures requires access to highly pure and sequence homogeneous DNAJB6b with no sequence extension. We therefore outline here an expression and purification protocol of the protein “as is” with no tags leading to very high levels of pure protein based on its physicochemical properties, including size and charge. The versatility of the protocol is demonstrated through the expression of an isotope labelled protein and seven variants, and the purification of three of these. The activity of the protein is bench-marked using aggregation assays. Two of the variants are used to produce a palette of fluorescent DNAJB6b labelled at an engineered N- or C-terminal cysteine.

Probable Reasons for Neuron Copper Deficiency in the Brain of Patients with Alzheimer’s Disease: The Complex Role of Amyloid

Alzheimer’s disease is a progressive neurodegenerative disorder that eventually leads the affected patients to die. The appearance of senile plaques in the brains of Alzheimer’s patients is known as a main symptom of this disease. The plaques consist of different components, and according to numerous reports, their main components include beta-amyloid peptide and transition metals such as copper. In this disease, metal dyshomeostasis leads the number of copper ions to simultaneously increase in the plaques and decrease in neurons. Copper ions are essential for proper brain functioning, and one of the possible mechanisms of neuronal death in Alzheimer’s disease is the copper depletion of neurons. However, the reason for the copper depletion is as yet unknown. Based on the available evidence, we suggest two possible reasons: the first is copper released from neurons (along with beta-amyloid peptides), which is deposited outside the neurons, and the second is the uptake of copper ions by activated microglia.

Synthesis and Characterization of Andrographolide Derivatives as Regulators of βAPP Processing in Human Cells

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder, one of the main characteristics of which is the abnormal accumulation of amyloid peptide (Aβ) in the brain. Whereas β-secretase supports Aβ formation along the amyloidogenic processing of the β-amyloid precursor protein (βAPP), α-secretase counterbalances this pathway by both preventing Aβ production and triggering the release of the neuroprotective sAPPα metabolite. Therefore, stimulating α-secretase and/or inhibiting β-secretase can be considered a promising anti-AD therapeutic track. In this context, we tested andrographolide, a labdane diterpene derived from the plant Andrographis paniculata, as well as 24 synthesized derivatives, for their ability to induce sAPPα production in cultured SH-SY5Y human neuroblastoma cells. Following several rounds of screening, we identified three hits that were subjected to full characterization. Interestingly, andrographolide (8,17-olefinic) and its close derivative 14α-(5′,7′-dichloro-8′-quinolyloxy)-3,19-acetonylidene (compound 9) behave as moderate α-secretase activators, while 14α-(2′-methyl-5′,7′-dichloro-8′-quinolyloxy)-8,9-olefinic compounds 31 (3,19-acetonylidene) and 37 (3,19-diol), whose two structures are quite similar although distant from that of andrographolide and 9, stand as β-secretase inhibitors. Importantly, these results were confirmed in human HEK293 cells and these compounds do not trigger toxicity in either cell line. Altogether, these findings may represent an encouraging starting point for the future development of andrographolide-based compounds aimed at both activating α-secretase and inhibiting β-secretase that could prove useful in our quest for the therapeutic treatment of AD.

Ferulago Angulata Methanolic Extract Protects PC12 Cells Against Beta Amyloid Peptide Induced Toxicity

Alzheimer's disease (AD) is an age-dependent neurodegenerative disease. Beta-amyloid peptide (Aβ)- induce neurotoxicity has a pivotal role in AD pathogenesis, therefore modulation of Aβ toxicity is the promising therapeutic approach for control of disease progression. Medicinal plants for having multiple active ingredients are effective in complex diseases such as AD therefore; several studies have been focused on medicinal plants for finding an effective treatment for AD. Ferulago angulata is a medicinal plant with the antioxidant and neuroprotective activity. The present study aims to assess the protective effect of the methanolic extract of Ferulago angulate on Aβ-induced toxicity and oxidative stress in PC12 cells. Methanolic extract of aerial parts of the plant was prepared by maceration method. PC12 cells were cultured according to a standard protocol. PC12 cells were incubated for 24 hours with Aβ alone, and Aβ in combined with various concentrations of the Ferulago angulata extract. Cell viability was determined by the MTT assay. Also, ROS production and the activity of Acetylcholine esterase (AChE), glutathione peroxidase (GPx), and caspase-3 enzymes were measured. The extract dose-dependently protects PC12 cells against Aβ-induced cell death. Also, Aβ increases the ROS production, AChE, and caspase-3 activity and decreases the GPx activity, which all were ameliorated by Ferulago angulata extract. Results of the present study indicate that Ferulago angulata extract protects against Aβ-induced oxidative stress and apoptosis. These effects may be due to the antioxidant and anticholinesterase activity of the extract. It is recommended Ferulago angulata extract be investigated more as an anti-Alzheimer agent.

Amylin Pharmacology in Alzheimer's Disease Pathogenesis and Treatment

: The metabolic peptide hormone amylin, in concert with other metabolic peptides like insulin and leptin, has an important role in metabolic homeostasis and has been intimately linked to Alzheimer’s disease (AD). Interestingly, this pancreatic amyloid peptide is known to self-aggregate much like amyloid-beta and has been reported to be a source of pathogenesis in both Type II diabetes mellitus (T2DM) and Alzheimer’s disease. The traditional “gain of toxic function” properties assigned to amyloid proteins are however contrasted by several reports highlighting neuroprotective effects amylin and a recombinant analog, pramlintide, in the context of these two diseases. This suggests that pharmacological therapies aimed at modulating the amylin receptor may be therapeutically beneficial for AD development, as they already are for T2DMM. However, the nature of amylin receptor signaling is highly complex and not well studied in the context of CNS function. Therefore, to begin to address this pharmacological paradox in amylin research, the goal of this review is to summarize the current research on amylin signaling and CNS functions and critically address paradoxical nature of this hormone's signaling in the context of AD pathogenesis.