ALZHEIMER’S DISEASE AND MICROGLIAL ACTIVATION

 Alzheimer’s disease (AD) is one of the most encountered irreversible neurogenerative diseases 1. However its complicated pathogenicity is not well-understood, amyloid-beta (Aβ) dysmetabolism, formation of extracellular Aβ deposits, presence of intracellular neurofibrillary tangles (NT), and neurodegeneration (ND) in the hippocampus and neocortex are involved in main processes in AD 2 3 4. Existence of the insoluble Aβ fibrillary aggregates in senile plaques is assumed as a major contributor of the neuropathology of the AD 5. Characteristic features of AD consist of cognitive deficits, impairment of executive functions, progressive memory loss, and reduction in the ability of daily life activities in the advanced stage of AD 4 6.

The formation of fibrils and aggregates takes place approximately 15 years before the appearance of symptoms of dementia 7. Mainly, the synaptic loss involved in the neuropathology of AD is considered to be associated with the severity of cognitive deterioration 5. There are several genetic risk factors associated with AD. Mutations in amyloid precursor proteins (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are considered as genetic risk factors in familial AD 8. Besides, many genes such as TREM2, CD33, CD2AP, etc. which are considered to cause higher AD risk take part in the regulation of elimination of misfolded proteins and regulation of inflammatory response .


Figure 1: Diagram of the hypothetical AD pathogenesis.

Some research with neuronal cultures showed that the picomolar concentration of Aβ is required for cell survival, increasing synaptic plasticity, memory, and learning 10 11 12. (Picomolar amyloid-beta positively modulates synaptic plasticity and memory in the hippocampus). In physiological conditions, Aβ decreases the potassium channels’ excitatory activity and diminishes neural apoptosis [1]. Others proposed that Aβ may possess antimicrobial activity, prevent leakage in the blood-brain barrier,  increasing recruitment after antimicrobial activity 13. Aβ peptides aggregate, accumulate and result in the formation of amyloid plaque and pathogenesis of AD 14. Defects in balance  between generation and clearance of Aβ peptides leads to β-amyloidosis 14.

A specific transmembrane protein called Amyloid Precursor Protein (APP) is the constituent of Aβ. α, β, and γ -secretases are proteases that play a major role in the fragmentation of APP 9. When the APP is cleaved by β, and γ -secretase, toxic and insoluble Aβ is produced and begins to aggregate 9. In the pathogenesis of AD, deficient phagocytic activity of microglia due to downregulation of phagocytosis receptors for Aβ and high cytokine level result in defective Aβ clearance 15. APP is a transmembrane glycoprotein and is split consecutively by β secretase which is the integral membrane aspartyl protease, also called BACE1 and γ-secretase complex which is membrane-bound protease complex is to generate Aβ 16.

There are many hypotheses about the development of AD. The main one is the Aβ cascade hypothesis which suggests that various risk factors such as inflammation, production of free radicals, oxidative stress, apoptosis, mitochondrial dysfunction contribute to the generation of Aβ 17. Besides, lower education level, cardiovascular disease, traumatic brain injury, diabetes mellitus can be also considered as contributors to the pathogenesis of AD or vice versa 18 19 20 21 22. Several neurodegenerative diseases consist of insistent overactivation of inflammation 23. Pathological alterations have the potential to stimulate synaptic loss, activation of microglia, mitochondrial dysfunction, neural death 24 25. Unfortunately, the exact mechanism behind the AD is still unknown 26.

Figure2: Diagram of the potential cause and effects of the microglial activation.

Microglia comprises nearly 15% of all glial cells in the central nervous system (CNS)  27. They become in a resting state in a stable microenvironment and alterations in the microenvironment result in microglial activation 26. They embody distinct forms in different inflammatory states

Figure 3: Main distinct forms of microglia and specific features of each form.

consisting of amoeboid microglia, ramified microglia, and activated microglia 28.  Ameboid microglia play important role in phagocytosis as scavenger 28. The form of microglia is mostly seen throughout brain development 28. Ramified microglia act as active macrophages and physically have long branches with narrow cellular bodies 28. They supply a stable microenvironment 28. Activated microglia release pro-inflammatory molecules and start the ‘’proinflammatory signal cascade’’ 28. They present antigen on their structure 28.

Several studies showed that microglial activation affiliates with AD pathogenesis 26. Microglia are a different phagocytic population that remove along with CNS and encountered close to Aβ plaques 28 29 30.  Microglia have the ability to clear off Aβ aggregates by way of phagocytosis or they can accelerate the accumulation of Aβ via spreading neurotoxic proteases and inflammatory molecules 31 32. Moreover, inflammation is considered as another major constituent of AD pathogenesis but it remains unclear whether it results from or results in AD 9 23 33. Although inflammation generally represses itself, it tends to be extended in chronic conditions and leads to liberating cytotoxic molecules which result in brain pathology 9.

Recently, the generality of the drug in the clinic is considered as a potential candidate for improvement of the symptoms and slow down improvement of AD. The drugs are based on affecting histaminergic or cholinergic system. Obviously, it is necessary to understand the exact mechanism of AD pathogenesis in order to find proper cure 34 35.

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Visual References:

  1. Gezen-Ak D, Dursun E. Molecular basis of vitamin D action in neurodegeneration: the story of a team perspective. Hormones (Athens). 2019 Mar;18(1):17-21. doi: 10.1007/s42000-018-0087-4. Epub 2018 Nov 27. PMID: 30484097.
  2.  Cai Z, Hussain MD, Yan LJ. Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer’s disease. Int J Neurosci. 2014 May;124(5):307-21. doi: 10.3109/00207454.2013.833510. Epub 2013 Sep 12. PMID: 23930978.
  3.  Cai Z, Hussain MD, Yan LJ. Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer’s disease. Int J Neurosci. 2014 May;124(5):307-21. doi: 10.3109/00207454.2013.833510. Epub 2013 Sep 12. PMID: 23930978.

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