INTRODUCTION:

Alzheimer’s disease(AD), which is named after the German psychiatrist Alois Alzheimer who first described this disorder, more than a century ago.¹ It is a neurodegenerative disease that starts and gets worsen over time in elderly people belonging to age group above 65. Alzheimer’s is predicted to affect 1 in 85 people globally by 2050.This disease is caused due to deposition of β-amyloid protein and tau protein inside the cell and leading to the cell death, which in-turn effects the cognitive function of the brain.^2,3AD is more commonly found to effect women population then men the hypothesis behind this is due to the imbalance or improper secretion of estrogen hormone after menopause.^4,5,6 The behavioural changes and hormonal levels are correlated i.e. mood swings, irritation during mensuration in women.

The lack of hygiene, poor health, depression, stress with increasing age is the main cause for more caregivers.^7,8,9 The diagnosis is based on cognitive testing with medical imaging, examination of brain tissues to know the definite understating of disease and with the help of biomarkers.¹⁰The disease is treated with the herbs having properties to cure the disease progression with lesser side effects. The main properties of plant that exhibits potential role towards AD are neuro-protective, antioxidants, anticholinesterase and the mechanism of action of these plants in AD is discussed below.¹¹

CAUSES:

The exact cause is unknown but it is understood that it develops because of a complex series of events that occur for a long period of time.

· Genetics: 50-79% of family history 0.1% forms of autosomal (not sex linked) dominant inheritance and onsets before age 65. The other genetic cause may be due to mutation.

Inheritance of E4 allele of the Apolipoprotein E (APOE) is in between 40-80% of people.

· Cholinergic hypothesis: This may also be caused due the reduced synthesis of acetylcholine (parasympathetic neurotransmitter).

· Amyloid hypothesis: Initiation of more number of aggregations of amyloid leading to generalized neuro-inflamation.

· Tau hypothesis: Tau protein abnormality initiates the disease cascade. The protein deposits can of two forms plaques and tangles. Plaques (accumulation of beta amyloid protein in the space between nerve cells and tangles (accumulation of tau protein inside the nerve cell).

· Other causes involves: smoking, the smoking is found to be the causes for dementia ,¹² air pollution, bacterium, head injuries, various vascular diseases like hypertension is also a cause for Alzheimer’s.¹³

· The oxidative stress in body leading to metabolic impairment causing disruption in calcium homeostasis may be found to be one of the causes for Alzheimer’s.¹⁴

DIAGNOSIS:

CLINICAL DIAGNOSIS:

This involves the study of patient history, collateral history from family and clinical observation based on the presence of characteristic neurological and neuropsychological feature and the absence of alternative conditions.

· Use of Biomarker (those measured in cerebral spinal fluid and plasma) can be used to detect AD.¹⁵Biomarkers used are Proteomics/cortical thickness and 4-Hydroxynoneal.^16,17

ADVANCED IMAGING TECHNIQUES:

Imaging with computer tomography (CT) or magnetic resonance imaging (MRI) will help to detect the changes in the size of brain region.¹⁸

· Single photon emission computed tomography (SPECT) or positron emission tomography (PET) can be used to differentiate Alzheimer’s from other types of dementia. Other is amyloid imaging.

PATHOPHYSIOLOGY:

1) NEUROPATHOLOGY:

· NEURITIC PLAQUES AND NEUROFIBRILLARY TANGLES

The loss of neurons in the cerebral cortex or in any part of brain is known as the neuropathological study .The neuropathology gives a gross atrophy of affected part. The degeneration is also present in brain stem nuclei like the locus coeruleus. These changes can be studied with the help of MRI and PET, this helps to detect size variation of specific parts of brain with people having Alzheimer’s.

Amyloid plaques and tangles are clearly viewed under the microscope in the brain of affected person. Plaques and tangles are insoluble accumulation of β-amyloid plaques ,which are denser.¹⁹ The abnormal aggregation of tangles along with the microtubule associated with tau protein start to become hyper phosphorylated and starts depositing inside the cell.^20,21

In elderly people there develops plaques and tangles as a consequence of their aging, but people with AD have greater number of them in specific parts of brain like temporal lobe.

In patients with Alzheimer’s show signs of vascular disease in addition to “classic” Alzheimer’s neuropathology.^22,23

· AMYLOID PRECURSOR PROTEIN:

AD is known as proteopathy (protein misfolding disease, caused due to the accumulation of abnormally folded beta and tau protein in the brain).²⁴

Amyloid precursor protein(APP) are the small fragments of β-amyloid .These proteins penetrates through the neuron’s membrane as these are transpermeable proteins.APP effects neurone growth, post injury repair. In AD, the process which makes the fragments of the APP is unknown, but the process is carried out by the enzyme proteolysis.²⁵Senile plaques are the deposition of broken β-amyloid pieces outside the neurons.

AD is also known as tauopathy due to the abnormal aggregation of tau protein.²⁶ Cytoskeleton made up of microtubules are the internal support of neurone. The function of these microtubules to act like tracks, guiding nutrients and molecules form the body of the cell to the end of axon and back. The tau protein is used in maintaining the internal structure of nerve cells (ALZ.ORG).

The tau protein stabilises the microtubule when phosphorylated and hence are known as microtubule associated protein.²⁷

In AD the tau protein undergo allosteric (some chemical change), these leads to the hyperphosphorelated which starts up the neurofibrillary tangles and disintegrating the neurons transport system.

· Oxidative stress or damages to cellular structures by toxic oxygen molecules called free radicals, is also regarded as a pathology characteristic of Alzheimer’s.^28,29,30

3) HYPERINSULINEMIA:

Neuronal cells depend on insulin to carry out main functions. The inability of insulin to bind to the neurons causes accumulation in the blood serum which is a condition known as hyperinsulinemia. Hyperinsuliemia in brain is predicted to stimulate inflammation which in turn stimulates neutritic plaques. Abnormal insulin signaling in the brain is associated with nerve cell dysfunction and death.

4) GENETIC VARIANTS:

Genetic variants are identified as the cause for both late and early onset cases of Alzheimer disease.

· A defect in gene known as APP, coding for protein amyloid precursor protein. This defect may effect in the production and deposition of amyloid beta leading to the formation of neutritic plaques.³¹

· A defect in the gene, which codes for apolipo protein E, Apo E(involved in the cholesterol transport).

· The 3 forms of this genes are- APOE2, APOE3 and APOE4, among which APOE3, APOE4 have the increased risk for causing this disease.

NEUROPATHOPHYSIOLOGICAL SCREENING:

· In-vitro screening: This method involves the screening of plant extract in TLC plate which will help to screen the number of plant extract to find more new acetyl cholinesterase inhibitor.³²

· In-vivo screening: This method involves the animal model for screening of plant extract.

STATISTIC:

Figure1: Shows percentage Age group of People effected with AD in US Population (2010-2050).

TREATMENT:

For treatment herbs are more preferred then synthetic drugs because of their lesser side effects and lesser toxicity.There are many synthetic drugs available in market but they only act to reduse symptamic cause of the disease and only focuses on decreasing disease progression not on the complete cure therefore the below discussed herbs can be used to treat AD and these drugs are plants with high neuroprotective, anticholinesterase and anti -oxidants property.

ANTIOXIDANTS:

Antioxidants are any substance that inhibits oxidation, especially used to prevent cell damage caused due to free radicals in the body.

· The oxygen molecule travel freely inside the body causing damage to the cell known as oxidative damage.

· The lower levels of antioxidants causes accelerated ageing, damaged or mutated cell, activation of harmful genes within DNA leading to increased risk for Alzheimer’s.

MECHANISM OF ACTION OF ANTIOXIDANTS IN ALZHEIMERS:

As oxidative stress is believed to play a central role in the pathogenesis of Alzheimer. The antioxidant rich herbs cause the depletion in free radicles causing cell death and reduces oxidative stress.

ACETYLCHOLINESTERASE INHIBITORS:

Anticholinesterase inhibitors are substances used to inhibit the acetyl cholinesterase enzyme from breaking down of acetylcholine.

MECHANISM OF ACTION OF ACETYLCHOLINESTERSE INHIBITOR IN ALZHEIMERS:

Acetylcholine levels plays an important role in Alzheimer’s when there is a lack of acetylcholine in synapse the anticholinesterase inhibitors increase the acetylcholine levels by inhibiting acetylcholineterase enzyme and thereby used for curing Alzheimer. Acetylcholinesterase inhibitors directly inhibits cytokine release and there by inhibiting the inflammatory pathway of AD.³³

NEUROPROTECTIVE AGENTS:

Neuroprotection refers to the relative preservation of neuronal structure and its function. Neurodegeneration occurs because of oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammatory changes, iron accumulation and protein aggregation. Neuroprotective agents target oxidative stress and excitotoxicity. Neuroprotective agents are substances used to protect neuronal damage.

MECHANISM OF ACTION OF NEUROPROTECTIVE AGENT IN ALZHEIMERS:

The neuroprotective agents act by reducing oxidative stress and by reducing excitotoxicity. Glutamate excitotoxicity is one of the most important mechanism behind cell death. The over excitation of glutamate receptors, specifically NMDA receptors, increases calcium ion influx due to the lack of specificity in the ion channel opened upon glutamate binding. Calcium ion accumulation inside the neuron causes improper regulation of cell process and eventually leading to the cell death.

HERBS USED IN ALZHEIMERS:

NAME OF THE PLANT

FAMILY

CHEMICAL CONSTITUTION

MECHANISM

USES

ANTIOXIDANTS

1.LEAVES:

· Camellia sinensis

(green tea leaves)

Theaceae

Epicatechin, epigallocatechin gallate,

Scavenging free radicals, regulating proper mitochondrial function, preventining deposition of protein plaques

Antioxidant,

Antiaging

· Cardiospermum halcababum

(ballon vine)

sapindaceae

Apigenin, proanthocyanidine, rutin

· Inhibitory effect on production of pro-inflammatory mediators

· Decreases plasma glucose and HbA1c,by increasing the levels of insulin and Hb.

Treates nervous disorders,

antirheumatoid,

antiinflammatory

· Ginkgo biloba

(ginkgo)

ginkgoaceae

Ginkgolides,bilobalides, biflavones , alkylphenols,polyprenols.

· It acts by enhancing congnitive functions.

Treatment of Alzheimer’s disease, antihypertensive,

2)ROOT

· Daucus carota

(wild carrot)

apiaceae

Carotoxin.

· It acts by reducing inflammation.

Anti-inflammation , depression

· Zingiber officinalis

(ginger )

zingiberaceae

Zingiberene, shagaol, gingerol.

· It acts by preventing loss of brain cells and anti-inflammatory response.

Motion sickness, carminative.

3)FLOWER

· Convolvulus pluricaculis

(shankhpushpi)

convolvulaceae

Hydroxyl cinnamic acid, octacosanol tetracosane.

· It acts by reducing mental fatigue and prevents brain cell damage , improves nerve cell function to increase its performance

Anti-stress, anti-depressive, anticonvulsant, memory enhancer.

· Viola sororia

(viola)

violaceae

Rutin,terpenes,ketone like ionone.

· It acts by neutralizing free radicals and thus preventing aging.

Antimicrobial, anti-asthmatic.

· Helichrysum italicum

(immortelle)

asteraceae

Isopropyl tetradecanoate, hexadecanoic acid,caryphyllene.

· It inhibits both enzymatic and non-enzymatic lipid peroxidation reaction and also acts as free radical scavenger.

Anti-microbial,

Anti-inflammatory.

ANTICHOLESTERASE INHIBITOR

1)LEAVES

· Carpolobia lutea

(cattle stick)

polygalaceae

Calacorene, alpha-beta deoxyglucopyranose,tannins, glycosides,alkaloids.

· It acts by inhibiting acetycholinesterase enzyme , hence increasing the acetycholine levels in the synapse.

Anti-diarrheal,antimicrobial,antidiabetic.

· Centralla asiatica

(brahmi)

Umbelliferaceae

Brahmosides, bramhminoside, thankunosides,asiaticoside.

· Reduces oxidative stress by acticing as acetycholinesterase inhibitor.

· It blocks lipoxygenase activity and lipid peroxidation reaction thereby it reduces beta amyloid levels.

sedative,anti-bacterial,blood purifier.

2)ROOT

· Wethenia sominifera

(ashwagandha)

solanaceae

Withanolides, withaferins,sitoindosides,Isopelletierine,annaferine,cuseohygrine.

· Inreasese acetycholine levels in the synapse.

Antihypertensive,antistress, anti-inflammatory.

3)FLOWER

· Narcisscus poeticus

(daffodills)

amaryllidaceae

Galatamine

· Cholinergic enhancer by inhibiting acetycholinesterase enzyme which hyrolyses acetycholine.

Anti-convulsant,anti-diarrhea,slows heart rate.

· Huperzia elmeri

lycopodiaceae

Huperzine A.

· Enhance memory and cognition by increasing the levels of neurotransmitors.

Myasthenia gravis, anti-inflammatory.

NEUROPROTECTIVE

1)LEAVES

· Opuntia ficus india

(Barbary fig)

cactaceae

Betalain,quercetin,isorhamnetin.

· Reduces blood sugar levels and LDL cholestrol.

· Offers resistance against infectious agents and sacvenges harmful l proinflammatory free radicals from the body.

Prevents scurvy, anti-inflammmatory, treatment in urinary tract infections.

CONCLUTION:

AD is one among the raising disease ,which cannot be prevented or cured .The present focuses of synthetic drug is on lowering the progression and not the complete cure, hence the herbs having neuroprotective ,acetyl cholinesterase inhibitor, and antioxidant properties can be used in the treatment of Alzheimer’s .These herbs found to have potential role in the treatment of Alzheimer’s.

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Received on 11.01.2018 Modified on 15.03.2018

Research J. Pharm. and Tech 2018; 11(6): 2695-2700.

DOI: 10.5958/0974-360X.2018.00498.5