Β-secretase inhibitors
As described above (see previous article), the proteolytic degradation of the Aβ precursor protein (APP) is mediated by the β-secretase involved in the first passage of the amyloidogenic pathway (later we saw γ-secretas intervening). Therefore, β-secretase also represents a potential therapeutic target. Currently, two drugs used to treat type 2 diabetes mellitus, roglitazone and pioglitazone, are being studied for mild to moderate Alzheimer's disease, although clinical studies have not yet shown beneficial effects. Specifically, rosiglitazone, better known as Avandia ®, is an oral hypoglycemic agent that stimulates the PPAR-γ receptor (peroxisomeproliferatedactivatedreceptor-γ). In Alzheimer's disease, Avandia is able to promote a reduction in the levels of Aβ42 (one of the fragments that are formed by the proteolytic cut of APP mentioned in the chapter on the pathogenesis of Alzheimer's disease). In a small study of individuals with mild Alzheimer's disease, patients who received Avandia showed higher levels of cognitive performance than the placebo group after 4 to 6 months of treatment. It should be noted that type 2 diabetes mellitus, insulin metabolism and Alzheimer's disease are related in several ways. In fact, epidemiological studies have shown that there is an increased risk of developing Alzheimer's disease in individuals with type 2 diabetes mellitus. Analyzing the adverse effects, a clinical study conducted on individuals with Alzheimer's disease showed that rosiglitazone is well tolerated, in fact the frequency of adverse effects in the treatment groups was not different from that observed in the placebo groups. Among the most considerable side effects, associated with the use of rosiglitazone, edema has been reported. Rosiglitazone, however, is a drug under investigation for its side effects on the cardiovascular system. For this reason, following a review by the EMA (European Medicines Agency), AIFA (Italian Medicines Agency) has forbidden the sale of all specialties containing rosiglitazone in Italy. In the United States, however, it remains on the market but subject to considerable restrictions. Another agonist of PPAR-γ, pioglitazone, better known for its trade name Actos ®, is being tested as a potential drug in Alzheimer's disease. Compared to rosiglitazone, pioglitazone has fewer adverse effects on the cardiovascular system. However, this drug appears to be associated with bladder cancer and for this reason it has been withdrawn in some countries including France, while in other countries its use is subject to restrictions on prescription and use.
Alpha-secretase stimulators
Before describing some drugs that act as a stimulator of α-secretases, it is worth mentioning that alpha-secretase is part of the alternative metabolic pathway of APP (Amyloid Precursor Protein), called the non-amyloidogenic pathway. In this way, the APP is degraded by the alpha-secretase which subsequently leads to the formation of a soluble N-terminal fragment and a transmembrane C-terminal fragment. Subsequently, the latter is degraded by the γ-secretase in two further non-toxic fragments.
It has been shown that two proteins, ADAM 10 and ADAM 17, belonging to the metalloproteinase and disintegrin family, are responsible for the α-secretase activity. Thus the stimulation of α-secretase and the consequent promotion of the non-amyloidogenic pathway of APP, represents a further potential therapeutic strategy based, currently, on the use of muscarinic receptor agonists of type M1, previously described. Etazolate has been shown to be a drug capable of stimulating α-secretase. It acts as a modulator of the γ-aminobutyric acid receptor (GABA).
It is known that with the progression of Alzheimer's disease, the proteolytic cut which occurs by the alpha secretase at the level of the amyloid precursor protein (APP), is considerably reduced, with a consequent increase in cognitive damage. This cleavage of APP occurs within the Aβ segment, thus preventing the formation of amyloidogenic fragments, and leading instead to the formation of sAPPα, a soluble fragment that is neurotrophic and pro-cognitive. It has been observed in some studies that low concentrations of etazolate stimulate the formation of sAPPα in neurons of animal models, showing that etazolate is also a neuroprotective drug.
Anti-inflammatory agents
NSAIDs (Non-Steroidal Anti-inflammatory Drugs). It has been observed that NSAIDs have a potential inhibitory activity towards the production of toxic Aβ fragments, but they can also counteract the inflammatory processes inherent in Alzheimer's disease, such as complement activation, chemokine expression, cytokine production and of nitric oxide. Therefore NSAIDs can also exert a protective action towards Alzheimer's disease, both by reducing the production of the Aβ42 (toxic) fragment, and by inhibiting the pro-inflammatory mechanisms, which also involve the activation of astrocytes and microglia. In some observational studies it was seen that individuals taking NSAIDs exhibited a reduced risk of Alzheimer's, although this was related to the duration of therapy, and considering at what stage of life they were taken. Among the NSAIDs that have been analyzed in the primary prevention of Alzheimer's disease, there are naproxen and celecoxib . However, these two drugs did not lead to cognitive improvements in older patients. Furthermore, it was also shown that the use of celecoxib increased the cardiovascular risk, so its use was interrupted in the early stages. Ibuprofen has also been tested for Alzheimer's disease prevention, but its use has not shown a significant improvement in cognitive performance.
Compounds that act on the tau protein
The Tau protein is responsible for the formation of neurofibrillary tangles, which are pathognomic features, together with the accumulation of β-amyloid plaques, of Alzheimer's disease. Under normal conditions, tau is part of the neuronal cytoskeleton. An abnormal and excessive phosphorylation of this protein favors its aggregation in paired double helix strands, which accumulate at the intracellular level forming neurofibrillary tangles. The latter promote cytoskeletal degeneration and neuronal death. Currently the potential compounds that act against the accumulation of hyperphosphorylated tau protein include kinase inhibitors that promote phosphorylation. These kinases include GSK-3 (glycogensynthase kynase-3) and CDK-5 (cyclin-dependent kinase-5). However, to date, few substances belonging to this class of compounds have been tested on humans. Among the molecules capable of inhibiting GSK-3, there is, for example, lithium hydrochloride, used for some mental disorders. As regards Alzheimer's disease, it has been observed that chronic administration of lithium induces a reduction in the hyperphosphorylation of the tau protein and also leads to an improvement in cognitive performance.
Valproic acid, another drug, was also able to inhibit GSK-3. Generally valproic acid is used in the treatment of epilepsy, but recently a group of English scientists has hypothesized that this compound is able to reverse the initial stages of Alzheimer's disease. Following a series of experiments carried out on animal models, which showed how the administration of valproic acid improved memory and led to a reduction in plaque formation, the scientific community has also begun to experiment on individuals suffering from Alzheimer's disease.
Another interesting compound appears to be methylene blue, a compound well known in laboratory practice, as it is generally used as a cell and tissue dye. In medical practice, on the other hand, its use is related to mouth ulcers and cystitis, while in the kitchen it is used as a dye. It was observed that oral administration of methylene blue, known under the trade name of Rember ®, slowed down the worsening of memory in individuals with Alzheimer's disease.
Methylene blue therefore appears to have anti-tau properties, preventing the formation of neurofibrillary tangles given by an abnormal phosphorylation of the tau protein, and when administered to individuals suffering from Alzheimer's disease induces a stabilization of neuronal degeneration.
