PATHOPHYSIOLOGY AND ETIOLOGY OF AD
Two main features of AD occur: one is the formation of plaque outside the cell, and the other is tangles formation inside the cell (Braak and Braak 1990). In AD, (3-amyloid peptides play important roles in its pathology. Mutations occur in the precursor of amyloid protein (Schenk, Barbour et al. 1999). Amyloid precursor protein (APP) has many functions, such as maintaining normal activity of neurons and aiding synaptic functions. If the APP is deficient, then structural and neuronal functional problems occur (Dong, Duan et al. 2012). Due to gene mutations, a 42-amino acid peptide forms, which is an important peptide present in the plaques of beta-amyloid in the brains of people with AD. In this condition, an amino acid at the original valine position is replaced by phenylalanine (Schenk, Barbour et al. 1999). Amyloid plaque interacts with synapse activity, causing loss of function inside the neurons, and ultimately apoptosis occurs. Levels of norepinephrine and serotonin become deficient due to loss of neurons and raphe nuclei present in the brainstem; due to this abnormal activity, loss of memory occurs, which is a major feature of AD. Vascular damage and a decrease in supply of blood to the brain are the initial features which cause impairment of memory, and the brain does not use glucose properly, resulting in damage to the neurons (Farkas and Luiten 2001). Usually, at an initial stage, when the cell cycle has been completed, differentiation of neurons occurs. In case of AD, however, at the G2 stage, progression of the cell cycle continues, and neuron differentiation may result in AD or neuron death (Nagy, Esiri et al. 1998). AD progression occurs as a result of mutations on chromosomes 1, 21, and 14 (Cummings, Vinters et al. 1998).
Different hypotheses suggest the operation of different mechanisms underlying the etiology of AD. However, it has been established that, at the histological and molecular level, the main abnormalities occurring are the extracellular formation of amyloid (3-peptide (A(3P) and the formation of neurofibrillary tangles inside the cells, ultimately leading to an extensive loss of cholinergic neurons in the hippocampus, cerebral cortex, and other areas of brain that are mainly involved in memory and cognition (Rui Wang, 2006).
Amyloid is basically an insoluble form of protein, that is formed as a result of abnormal folding of polypeptides which are normally present. The precursor of amyloid is called Beta-Amyloid Precursor Protein ((3APP) that ultimately gives rise to amyloid proteins (Yuhai Zhao, 2014).
(3-APP is encoded by a gene present on the 21q chromosome arm. Due to gene mutations, structural rearrangements, or even deletions, an increase in the number of genetically altered mRNAs encoding (3APP are produced in some specific tissues or cells. The abnormal (3APP polypeptides are formed which, when presented for proteolytic processing, are cleaved, mostly at residue 687 of the (3APP, thus preventing the formation of A(3P. This is what normally happens but, sometimes, overuse of alternate proteolytic pathways leads to the production of large amounts of A|3P contained in C-terminal fragments. This A(3P is then accumulated in several brain regions, forming the amyloid plaques. The microglia and astrocytes at the site of these abnormal plaques are activated and some A(3P-associated proteins are also attracted to accumulate in said plaques. These plaques cause degeneration of the incontact neurons of cortical and subcortical regions of the brain. Many neurons are affected but studies have associated the clinical signs and symptoms of AD with the loss of cholinergic neurons in the cerebral cortex and hippocampus. The degenerative changes in the neurons start by the formation of the neurofibrillary tangles, that are formed by the hyperphosphorylation of the tau proteins that are normally involved in the formation of microtubules inside neurons. As a result, microtubule formation is disturbed, leading to impaired communication and loss of neuronic function. All these changes occur over several years, to ultimately result in the clinical manifestation of AD (Selkoe, 1991).
The decrease in the number of cholinergic neurons was the first indicator of AD discovered in the struggle to uncover the mechanism of the disease. Because these neurons are associated with keeping the short-term memory intact, it was established that the loss of short-term memory that occurs in AD was associated with the loss of these neurons. The degenerative process is seen to start in the entorhinal cortex and nucleus basalis. In advanced AD, the loss of cholinergic neurons may reach up to 90%, leading to the symptoms of dementia. In patients with AD, the concentrations of acetylcholinesterase and choline acetyltransferase were found to be low, and continued to decline further with the advancement of the disease. Recent pharmacotherapy aims to compensate for the loss of these cholinergic function losses by increasing concentrations of the neurotransmitter acetylcholine by introducing cholinesterase inhibitors, precursors of acetylcholine or agonists of nicotinic and muscarinic receptors (Abbasi, 2006), but, because multiple neurons are affected and not just those of the cholinergic types, only management of the symptoms of dementia associated with the disease is achieved, and the patients cannot find complete relief (Selkoe, 1991).
In AD, the main symptom which appears in patients is loss of memory and it occurs due to damage to brain tissue. Initially, patients have problems remembering those events which occurred recently; after this, slow' progression of the disease occurs, and it becomes more severe. Some other problems, like loss of thinking, e.g. remembering numbers, are very difficult for a patient. Patients cannot carry out more than one task at a time, and also have difficulties in remembering the names of their family members, with problems also occurring in decision making, judgment calls, etc. A major issue is changes in personality, such as social withdrawal, not wanting to meet w'ith other people, and remaining sad and depressed all the time (Simonson 2018). Patients also have difficulty with speech and reading, and their w'riting skills are also affected (Seshadri, Drachman et al. 1995). Patients can also have problem with sleeping, whereas language problems initially occur (Wint and Tavee 2014).
In epidemiological studies, it is observed that dementia occurs as part of this disease. It is an age- related disease, mostly affecting people after the age of 60 years, and the proportion of the population with this disease is increasing every five years. Many factors are involved in the progress of this disease, namely educational factors, drugs, genetic, and environmental factors. If patient had a previous head injury, then this can also trigger AD (Dong, Duan et al. 2012). Females are more commonly affected than males (Wint and Tavee 2012).
Many synthetic medicines are available which have effective roles in the management of dementia. So far, the treatment of AD has been carried out by using cholinesterase inhibitors, a strategy which is approved by the Food and Drug Administration of the US. Other chemicals, such as vitamin E, anti-inflammatory drugs, and selegiline (an enzyme blocker which slows the breakdown of some neurotransmitters), have been studied for their usage but their use is still not fully approved. Many herbal plants have been tested for the treatment of AD. Extracts from these plants can prevent this disease. Many herbal plants have important chemical constituents w'hich have pharmacological roles, and these constituents can act in inhibitory or excitatory ways. Several plants are being trialed for the treatment of AD and these are discussed in the rest of this chapter (Geun Kim and Sook Oh
MEDICINAL PLANTS WITH ANTI-ALZHEIMER'S DISEASE POTENTIAL
Hypericum perforatum (St. John's Wort)
H. perforatum plant is a herb, and the height of this plant is up to 80 cm. The shape of the leaves of this plant is like a spoon. The most important constituents of this plant are choline, hypericin, hyperforin, flavonoids, tannins, and essential oils, obtained from the leaves of this plant. All the constituents of the plant have important role in the treatment of brain diseases, because they have properties to treat anxiety and depression, and to achieve relief from inflammation. Quercitrin and quercetin are both important flavonoids obtained from this plant which have antioxidant activity, inhibiting the oxidation of lipids. Thirty minutes before giving an injection of 1.4 mg/kg body- weight scopolamine to induce oxidative stress, the patients were first treated with H. perforatum extract at dosages of 4 mg/kg, 8 mg/kg, or 12 mg/kg, which proved to be effective in the treatment of oxidative stress. Hyperforin has been used to treat memory loss, and this plant can play an important role in the treatment of AD (Jivad and Rabiei 2014).
Curcuma longa (Turmeric)
C. longa, also commonly known as Haldi in Urdu, belongs to the ginger family Zingiberaceae, and is known as a powerful antioxidant and anti-inflammatory (Singhal 2012). Studies to uncover the underlying mechanism of AD have established the presence of activated microglia and astrocytes surrounding the beta-amyloid plaques, indicating that amyloid plaques are the sites of chronic inflammation (Selkoe 1991). C. longa acts as an anti-inflammatory, thus lowering the inflammation associated with AD. Moreover, free radicals in the body are identified to be one of the reasons behind the gene mutations, leading to production of abnormal A(3P in the brain. Being a powerful antioxidant, turmeric can lower the oxidative stress inside the body, thus preventing or suppressing development of the disease.
Curcumin from C. longa rhizomes, also known as diferuloyl methane, has shown anti-inflammatory effect, whereas polyphenolic components obtained from turmeric have also shown beneficial effects in the treatment of AD. In AD, plaque is formed and this amyloid plaque can be removed by treatment with curcumin, which stimulates macrophages to remove foreign particles. Macrophages are a part of our immune system and have the tendency to remove abnormally formed plaque. By removing this plaque, it may be possible to prevent AD (Geun Kim and Sook Oh 2012).