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Pharmacological aspect of Alzheimer’s Disease
Ali Musallam Alsalem 2160006894 3rd year

Alzheimer’s disease defined as severe degeneration of neuorons and nural tissues especially at the brain that will lead to tissue damage and mental loss, functional behavioral and learning ability decline and eventually it’s lead to dementia. Therefore, the pathological features of this disease characterized by neurofibre tangles intracellularly and senile plaques formation due to amyloidal protein deposition extracellularly. Amyloid palques are depostion of A? in the parenchyma of the brain and in the blood vessels at the cerebrum. It’s known as congophilic angiopathy and cerebral amyloid angiopathy (CAA). Some studies suggest that alzheimer’s disease is related with insufficient levels of neurotransmitter.
There is several hypotheses that explain pathophysiology of this disease such as A ?-amyloid hypothesis, cholinergic hypothesis, and inflamation hypothesis. The commonest used hypothesis is A ?-amyloid hypothesis. Recently, this hypothesis doesn’t work for the very complex pathophysiology of this disease. So, some studies foucus on the role of A ?-amyloid oligomers in synaptic impairment especially. These are the only signals that destroy brain function integrity and at later age the amyloid plaques formation will take place as a late event. However, the amyloid casecade hypothesis suggest that the APP is cleaved by ?- secretase normally and processed by ?- and ?- secretase. The result will be imbalance between clearance and production of A ?-amyloid peptide. Consequncely, A ?-amyloid peptides aggregate into soluble oligomers spontaneously and coalesce to form insoluble ?-sheet fibrils conformation and there will be deposition in diffuse senile plaques eventually. Ther are several pathoways that help in removing of A? from brain including IDE (insulin degrading enzyme), cereprospinal fluid (CSF ) flow passivly, uptake by microglia and astrocyte, and sequestration into the vascular compartment by soluble form of LRP1 (low density lipoprotein receptor related protein 1).
Classification of AD drugs:
A) Anti-amyloid (A ?-amyloid protein):
Amyloid transport as a target:
Due to aging the expression of (low density lipoprotien receptor related protein) LRP decreases, leading to impair A ?-amyloid oligomers efflux that will lead to retension of this material in the brain. Therefor, Antibodies against (low density lipoprotien receptor related protein) will reduce A ?-amyloid oligomers efflux from the brain eventually, this can be as a target for treating alzheimer’s disease.
Secretase enzyme modulation as a target:
The cell surface receptors (GABA agonist \ muscarinic) and the activation of cascades signling like PKC will regulate the activity of ?- secretase. PKC potent activator is bryostatin1 also it is an anti cancer agent.
Aggregation of amyloid as a target:
Proline or (CLN) colostrinin rich complex polypeptide and it’s came from an isolation of ovine colostrum. It affects congitive function, memory and learning due to having a strong immunoregulatory properties. A ?-amyloid peptides aggregation and dissolve pre-formed fibrils inhibited by colostrinin.
Clearnce of amyloid as a target:
In pateint with alzahimer disease the level of A ?-amyloid oligomers degrading enzyme decrease which will lead to A ?-amyloid accumlation. So, the inhibition of plasmainogen activator 1 will decrease the brain and plasma A ?-amyloid oligomers level. Some studies show (somatostatin) the peptide hormone will regulate A ?-amyloid oligomers clearnce through neprilysin activation.
Vaccination therapy of amyloid as a target:
Inducing an immunity response due to vaccination therapy of individuals with A ?-amyloid oligomers will causes inhibition of A ?-amyloid oligomers and it is clearnce from the body. The cerebrospinal levels of tau protiens and a slower congnitive decline due to using A ?-amyloid42 peptide generated anti- A ?-amyloid antibodies as a treatment.
B) Tau protein:
Tau protein can lead to exellant theraputic drug because it’s synthezied by neuronal cells. It’s function to stabilize the microtubules for perfect function of the neurons, specificly in axonal morphology, polarity and growth.
Tau phosphorylation inhibition as a target:
(GSK3) glycogen synthase kinase 3 is an enzyme that contribute in phosphorylation of tau protein. By experiment, valproate and lithium have an inhibition effect on glycogen synthase kinase 3 and reduce the tau pathological properties.
C) Level of nurotransmitter modulation:
(AChEIs) Acetylcolinesterase inhibitors:
Inhibition of Acetylcolinesterase enzyme will enhance colinergic neurotransmission and finally this will lead to decreasing the Acetylcolin breakdown. Examples of drugs: (rivastigmine, galantamine, tacrine and donepezil).
GABAergic neurons modulation:
Inhibitory GABA transmission change to excitatory stimulus due to chronic GF deprivation. A neuroprotective pharmacological drug that called Etazolate. It cause activation of ?- secretase , inhibition of (PDE)-4 activites and modulation of GABAA receptors.
Antagonism of NMDA receptors:
Synaptic plasticity, differentiation, memory, neuronal growth, congnition and learning regulated by glutamatergic neurons. An uncompetitive NMDA antagonist called Mematine. It blocks the receptors due to trapping it in open conformation.

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Treatment by Anti-inflammatory drugs:
The antiinflammatory drugs have variety of mechanism of action other than inhibition of cyclooxygenae(COX) like target the ?- secretase, Ca2+ homeostasis and PPAR. They manage this disease by astrocyte motility, phosphorylation of tau protien and axon growth.
Nitric oxide modulators:
The (NO) has many function in the central nervous system for example: neurotransmitter secretion, appetite control, coginitive function and neuroprotictive. Nitric oxide can help in the protection of neurons from excitotoxicity by effect of NMDA receptor inhibition.
Cholesterol decreasing drugs:
Statins have good effect on memory, neuroprotection, and cognition by pleiotropic and dose dependent effects. They are have other beneficial properties due to protecting the primary cortical neurons from toxicity of glutamate.
General side effects:
Tacrine (Cognex) rarely prescriberd due to it cause liver damage.
A ?-amyloid can cause inflammation and neuoral death.
High doses of cholesterol decreasing drugs can cause serious problems.
Activation of (iNOS) will lead to excess of nitric oxide eventually cause immunodulation and neuronal damage.

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