Review article
Alzheimer’s disease and its treatment by different approaches: A review

https://doi.org/10.1016/j.ejmech.2021.113320Get rights and content

Highlights

  • Alzheimer’s disease (AD) is a neurodegenerative disorder that impairs neurocognitive ability.

  • Major hypotheses about causes of AD are cholinergic, amyloid, tau hypothesis.

  • Diagnostic biomarkers for neurological disordersincludes Aβ and tau proteins, Fyn kinases etc.

  • Calcium signaling, TDP-43, BACE1, angiotensin converting enzyme are active molecular targets against AD.

  • Stem cell therapy and nanodrug delivery might be a promising candidate for AD therapeutics.

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder that impairs mental ability development and interrupts neurocognitive function. This neuropathological condition is depicted by neurodegeneration, neural loss, and development of neurofibrillary tangles and Aβ plaques. There is also a greater risk of developing AD at a later age for people with cardiovascular diseases, hypertension and diabetes. In the biomedical sciences, effective treatment for Alzheimer’s disease is a severe obstacle. There is no such treatment to cure Alzheimer’s disease. The drug present in the market show only symptomatic relief. The cause of Alzheimer’s disease is not fully understood and the blood-brain barrier restricts drug efficacy are two main factors that hamper research. Stem cell-based therapy has been seen as an effective, secure, and creative therapeutic solution to overcoming AD because of AD’s multifactorial nature and inadequate care. Current developments in nanotechnology often offer possibilities for the delivery of active drug candidates to address certain limitations. The key nanoformulations being tested against AD include polymeric nanoparticles (NP), inorganic NPs and lipid-based NPs. Nano drug delivery systems are promising vehicles for targeting several therapeutic moieties by easing drug molecules’ penetration across the CNS and improving their bioavailability. In this review, we focus on the causes of the AD and their treatment by different approaches.

Introduction

Alzheimer’s disease (AD) is declared as “global public health priority” by WHO, because there is no permanent remedy for AD. So far, there are only well-stated concepts and hypotheses about the cause and drug targets of AD. Based on this concept, medications reduce disease pathology progression [1]. AD is the primary cause of dementia in people above the age of 60. Around 50–75% of people with dementia have Alzheimer’s. As per the statistical data collected worldwide, females are more prone to AD than males, and the risk increases even more with age [2]. People with cardiovascular diseases, hypertension, and diabetes are also at higher risk of having AD later. This probably is the leading cause of increased AD cases in developing countries, owing to people’s lifestyle [3]. Patients with clinical symptoms similar to Alzheimer’s but not showing any pathophysiology related to the disease, can be the individuals who are concerned about apparent loss of memory even when there is no substantiation for impairment. This condition is known as ‘worried well’, the effects of alcohol and drugs, and the people with affective illnesses show such symptoms [4]. Other neurodegenerative disorders with AD like symptoms include frontotemporal dementia and lewy body dementia; inflammatory, metabolic and infectious condition; vascular cognitive impairment; and a series of causes that include obstructive sleep apnoea and transient epileptic amnesia [5].

The presence of Aβ40 aggregates and tau protein fibrils makes up the primary pathological condition of AD. However, the company of any one of them can be due to any non-AD and age related dementia [6]. Their link to any neurodegenerative disorder is not clear. The pathological changes occur long before the actual appearance of the symptoms. Various medical approaches that target these pathological processes have proved unsuccessful in preclinical or clinical trials, mainly because of the low bioavailability, blood-brain barrier penetration, imperfect cell, and low half-life of the drug in present treatments. Therefore, the requirement to have new disease-modifying therapies to avoid the development or lower the pace of these enervating disorders’ is essential.

The convergence of stem cell therapy and nanoparticles holds great promise for studying, diagnosing, and treating neurodegenerative disorders [7]. A rising amount of pre-clinical studies have recommended that transfer of neural stem cells (NSCs) can pose a potential new treatment for neurodegenerative disorders. Though the early anticipation concerning this therapy concentrated on employing NSCs to restore degenerating neurons, the latest reports have associated NSC regulated variations in neurotrophins as an active therapeutic effectiveness [8].

The nanoparticles (NPs) regulated drug delivery techniques enhance bioavailability and drug solubility, hence rendering them greater options [5,9]. Additionally, NPs regulated strategies mediate multiple drugs loading and targeted drug delivery, hence enhancing drug effectiveness. Though, particular NPs can produce grave toxicity deteriorating cellular and tissue organization [10,11]. Thus, NP material should be selected carefully. Also, neurodegenerative disorder occurs due to the misfolding of the protein [12,13]. Nanoparticles are suitable candidates for protein refolding by the second route due to their large surface area and minimum diffusional limitation which facilitate better interactions with charged residues on the surface of the denatured protein [[14], [15], [16], [17]]. In the present review, we discussed the causes of the AD and their treatment by different approaches.

Section snippets

Causes of Alzheimer’s disease

A rational chronological order of the occurrences in AD, along with an acceptable and efficient therapy, is lacking. Interaction of oligomers of Aβ protein with glial cells and neurons results in various pathological and physiological anomalies, comprises mitochondrial dysfunction, stimulation of pro-inflammatory cascades, increased tau phosphorylation and oxidative stress, de-regulation of calcium metabolism, enhanced glycogen synthase kinase (GSK)-3β activity, stimulation of cell death and

Alzheimer’s diseases treatment

Combination therapy is required for the successful treatment of AD, since multiple factors influence the progression of the disease. Multi-targeted drugs can be looked forward to for dealing with multiple symptoms and causes of the disorder. BACE1 has been so far the primary therapeutic target for AD therapies, against Aβ accumulation. However, all the potential drugs developed have not been successful beyond phase II/III trials. The challenges faced still involve low bioavailability, increased

Conclusion and future prospects

While our knowledge of AD has considerably grown over the past years, it still continues to be anything but complete. Most of the unsuccessful phase 3 trials employing monoclonal antibodies targeting Aβ have driven scepticism about the hypothesis. It is noticeable, that patient selection and target engagement complicated a lot of analysis, and a part of patients employed for the trials did not have evidence for AD pathology. However, during most analysis patients with later stage AD were

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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