“New Pathway in Treating Alzheimer’s Disease-Moving Beyond Amyloid Strategy”

or, alternatively, the use of multi-target drugs, i.e. when one drug restores several of these mechanisms. Recent studies have shown that many drugs used in clinical practice to treat various diseases can also inhibit the main mechanisms driving the progression of neurodegeneration. Majority of these drugs have been used in medicine for years, so their pharmacokinetics, toxicity and side effects, as well as their therapeutic dose range, are well understood. As a result, they can be relatively quickly introduced to the treatment of AD. It should be noted that a number of widely-used drugs from various pharmacological groups, “in addition” to the main therapeutic indications, also have a proven beneficial effect on neurodegeneration and may already be introduced into clinical practice in combination therapy of AD. There is a real hope that the Abbreviations: AD: Alzheimer’s Disease; MAO B: Monoamine Oxidase B; MPTP: Pathway in Treating Alzheimer’s Disease-Moving Beyond Amyloid Strategy”.


Introduction
Despite extensive research, no new drugs for the treatment of Alzheimer's Disease (AD) have been introduced into therapy for over a decade. Nevertheless, the results of recent studies on the patho mechanism of Alzheimer's disease progression may raise some hopes as they identify and expose several major pathways of brain tissue homeostasis dysfunction, pathways that should undergo pharmacological correction to slow or inhibit the progression of neurodegeneration. While in the early stages of Alzheimer's disease, increased synthesis and oligomerization of β-amyloid and hyperphosphorylation of the tau protein play a key role in the patho mechanism of the disease, it is in the later stages of the disease that several known dysfunctions of the major Insulin resistance of the brain leading to disturbed metabolism of neurons d) Reduction of the activity of the catenin Wnt-β pathway, which should properly integrate the above homeostatic mechanisms of brain tissue cells.
In order to more effectively inhibit the progression of neurodegeneration, it is necessary to use a combination therapy consisting of several drugs correcting the above dysfunctions or, alternatively, the use of multi-target drugs, i.e. when one drug restores several of these mechanisms. Recent studies have shown that many drugs used in clinical practice to treat various diseases can also inhibit the main mechanisms driving the progression of neurodegeneration. Majority of these drugs have been used in medicine for years, so their pharmacokinetics, toxicity and side effects, as well as their therapeutic dose range, are well understood.
As a result, they can be relatively quickly introduced to the treatment of AD. It should be noted that a number of widely-used drugs from various pharmacological groups, "in addition" to the main therapeutic indications, also have a proven beneficial effect on neurodegeneration and may already be introduced into clinical practice in combination therapy of AD. There is a real hope that the applied multi-drug therapy will effectively inhibit the progression of AD and turn it into a slowly progressing chronic disease.  apoptotic Bax proteins [3]. Rasagiline also exerts neurotrophic activity by stimulating alpha-secretase to produce Soluble, neurotrophic APP-α (sAPPα), which is supported by PKC and MAP kinases. Rasagiline's neuroprotective, neurotrophic and anti-apoptotic effects are independent of MAO inhibition [3].

Examples of a Multifunctional Drug that Affects Several Different Factors / Mechanisms of AD Pathogenesis Include
Rasagiline is currently in the second phase of clinical trials in patients with mild to moderate AD. c) Glitazones (thiazolidinediones): rosiglitazone, pioglitazone, troglitazone, are agonists of PPARγ (peroxisome proliferator-activated receptors) and activation of PPARγ reduces BACE1 transcription and activity [4,5]. Literature data indicate a beneficial effect of rosiglitazone and pioglitazone on the improvement of memory and learning abilities in murine AD models [5]. Additionally, it was found that in cultures of neuronal cells, the studied glitazones inhibited the key pathways of AD pathomechanism -rosiglitazone significantly decreased BACE1 transcription, thus decreased amyloidogenesis [5], and pioglitazone inhibited tau hyperphosphorylation and its oligomerization [6]. d) Drugs that restore the activity of the Wnt pathway (lithium chloride, sodium selenate, rosiglitazone) may also have a multifunctional effect on the mechanisms of neurodegeneration.

Restoration of Wnt signaling inhibits BACE1 expression, reduces
Aβ production and aggregation, inhibits the activity of GSK3β kinase and reduces tau hyperphosphorylation [7], at the same time the Wnt system significantly improves cell regeneration and neuronal survival, increases the sensitivity of neurons to insulin, increasing the expression and activity of hexokinase and other glucose metabolism enzymes [8], and significantly reduces inflammatory reactions in the brain [9][10][11][12][13][14]. Alzheimer's disease brain [15,16]. Therefore, despite initially