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Alzheimer’s Disease: Mechanism of Pathophysiology Prevention Treatment

            Alzheimer’s disease is described as a neurodegenerative disease, which is a major cause of progressive dementia. Progressive neurodegeneration is due to accumulation of tau neurofibrillary tangles and beta amyloid proteins (Tiwari et al., 2019).  The purpose of this paper is to discuss the normal anatomy and physiology of the major body systems affected by Alzheimer’s disease, pathophysiology of the disease, prevention, and treatment of the disease. Alzheimer’s disease is a progressive neurodegenerative disease that can lead to loss of neurons, synapses, and even death. 

Normal Anatomy of Major Body System Affected

            Amyloid proteins are normally soluble proteins. However, in Alzheimer’s disease, the defective amyloid proteins are insoluble and forms plagues. Misfolding amyloids proteins make them insoluble (Tiwari et al., 2019).  The amyloid precursor proteins are a family of proteins that share similar structure and many overlapping functions. Amyloid precursor proteins are processed by canonical and non-canonical secretases, which lead to production of many biologically active fragments, which mediate different and sometimes opposing functions. Membrane-bound amyloid precursor proteins normally interact in trans or cis conformation, enabling them to function as cell-adhesion molecules (Müller et al., 2017). α-Secretase cleavage cleaves amyloid precursor proteins releasing the neurotrophic and neuroprotective fragment amyloid α (Müller et al., 2017).

Normal Physiology of Body System Affected

            Healthy people free of Alzheimer’s disease have properly folded and functional amyloid proteins, which are necessary for normal brain function (Tiwari et al., 2019). Amyloid precursor proteins and the amyloid precursor-like proteins forms the mammalian amyloid precursor protein gene family. Amyloid precursor proteins play an important role in terms of normal physiological function of the central nervous systems and the peripheral nervous system, of which specific functions are still emerging (Müller et al., 2017).  Biological functions in which amyloid proteins play a role include function and formation of the neuromuscular junction; development of the system development; synaptogenesis; spine density; dendritic complexity; synaptic functions; and axonal growth. They are also important in learning and memory and synaptic plasticity (Müller et al., 2017). Amyloid α inhibits neuronal apoptosis, upregulates protective pathways, has a crucial role in synaptic plasticity, increases neuronal resistance to brain injuries, and is important in learning and memory. Increasing amyloid α proteins may have therapeutic value (Müller et al., 2017).

Pathophysiology

            Alzheimer’s disease is a neurodegenerative disease that develops as a result the accumulation of extracellular amyloid β plagues and the intracellular neurofibrillary tangles composed of hyperphosphorylated τ-protein in the limbic and cortical areas of the brain (Tiwari et al., 2019). Amyloid precursor protein is converted to amyloid β peptide, which plays an important role in development of Alzheimer’s disease (Müller et al., 2017). The abnormal processing of amyloid precursor protein by the γ-secretases and β-secretases result in synthesis of amyloid β40 and amyloid β42 monomers. These defective proteins are furthermore oligomerized and accumulated into senile plagues.  Neurofibrillary tangles are made up of hyperphosphorylated microtubule-related tau (τ) (Tiwari et al., 2019).  Neurofibrillary agglomerates and amyloid plagues are the two most important microscopic features that are helpful in the diagnosis of Alzheimer’s disease (Picanco et al., 2018).

            Amyloid β proteins develops initially in the temporal, orbitofrontal neocortex, and basal regions of the brain. In late stages of the disease, amyloid β deposition progresses throughout the hippocampus, neocortex, amygdala, basal ganglia, and diencephalon. In critical cases of Alzheimer’s disease amyloid β accumulates throughout the lower brain stem, mesencephalon, and cerebellar cortex. On the other hand, it has been established that concentration of amyloid β stimulates formation of τ tangle, which is deposited in the entorhinal area, transentorhinal area, and the locus coeruleus. In the critical stage of the disease τ tangles spread to the neocortex and hippocampus. Amyloid β and neurofibrillary tangles are considered as the important player in the development of Alzheimer’s disease (Tiwari et al., 2019).

            Overproduction of amyloid β proteins results in production of amyloid plagues, which can in turn result in neuronal damage and death. Mislocalization of tau (τ) proteins to the dendrites results in spinal loss which is associated with neuronal damage and even death. In addition, hyperphosphorylation of τ proteins results in instability of microtubules and eventually the microtubule subunits breakdown resulting in the formation of insoluble as well as large neurofibrillary tangles, which contribute to damage to neurons and even death (Tiwari et al., 2019).  The disease is characterized by loss of synapse, loss of neurons due to due to accumulation of neurofibrillary tangles and amyloid β (Chen, 2018).

            The onset of Alzheimer’s disease and its progression involves a complex interplay of different factors such as genetic mutations, aging, social factors, metabolic disorders, and nutritional disorders. In addition to aging factors such as obesity, hypertension, diabetes, and different inflammatory disorders may contribute to development Alzheimer’s disease (Tiwari et al., 2019).  The disease is also thought to develop as a result of oxidative stress, mitochondrial dysfunction, inflammatory mechanisms, and/or autophagy (Chen, 2018). Yu and colleagues (2020) identify eight risk factors of Alzheimer’s disease including depression, diabetes, stress, head trauma, hypertension in midlife, hypotension, coronary artery bypass grafting, and midlife obesity.

The disease is characterized by progressive neurocognitive dysfunction and memory loss. Decrease in DNA methylation seem to deteriorate neuronal plasticity, resulting in loss of memory. Apart from memory loss, other signs and symptoms of the disease include loss of language abilities/skills, hallucinations, and disorientation. (Tiwari et al., 2019). Slow and progressive amyloid plague accumulation and neurofibrillary conglomerates are attributed to memory loss which affects personality, cognitive control and language (Picanco et al., 2018). The condition can also cause behavioral disability and cognitive dysfunction (Chen, 2018).

Prevention

            Prevention strategies include cognitive activity and use of total homocysteine lowering drugs such as vitamin B12, folic acid, and vitamin B6. Physical activity and cocoa flavanol have significant impact in reducing the risk of Alzheimer’s disease. Other strategies that can promote prevention of Alzheimer’s disease include use of non-steroidal anti-inflammatory drugs, antihypertensive treatment, ginkgo biloba, acetylcholinesterase, and hormone replacement therapy (Yu et al., 2020).

Treatment

            A large proportion of Alzheimer’s disease therapeutics focus on lowering the levels of toxic forms of amyloid β and τ proteins. Several drugs have been developed to manage or treat the disease. These drugs include aducanumab is a monoclonal antibody in Phase I drug trial with antiamyloid activity. Other antiamyloid drugs in Phase I drug trials include albumin and immunoglobulin (polyclonal antibody); AZD3293 (BACE1 inhibitor); CAD106 (amyloid vaccine); CNP520 (BACE inhibitor); E2609 (BACE inhibitor); Gantenerumab (monoclonal antibody); Nilvedipine (monoclonal antibody); and Solanezumab (monoclonal antibody). Antiamyloid medications in Phase II drug trials include ATP (amyloid misfolding and toxicity); Atomoxetine (adrenergic uptake inhibitor); AZD0530 (kinase inhibitor); Crebezumab (BACE inhibitor); UB311 (monoclonal antibody); and Valacyclovir (antiviral agent). Other antiamyloid agents in Phase III trials include KHK6640 (amyloid-aggregation inhibitor); Lu AF20513 (polyclonal antibody); LY2599666 and solanezumab (monoclonal antibody combination); NGP 555 (γ-secretase modulator); and MK8931 (BACE inhibitor) (Tiwari et al., 2019). Medications that are in use currently include donepezil, galantamine, and rivastigmine. However, they are plagued by treatment failures (Tiwari et al., 2019).

Conclusion

Alzheimer’s disease is protein-conformational and a neurodegenerative disease which is associated with neuron damage and death due to accumulation of amyloid β and neurofibrillary tangles.  It is a major cause of dementia. The disease is characterized by symptoms such as progressive memory loss and neurocognitive dysfunction.  Many drugs are currently under development, Phase I to III, for management of Alzheimer’s disease. Medications that are currently used to manage Alzheimer’s disease include donepezil, galantamine, and rivastigmine.