Immunology of Alzheimer's Disease

Microglial Cells
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Figure 1. Microglial cells interact with neurons within the CNS

Alzheimer’s disease (AD) is a common form of dementia mostly found within patients over the age of sixty-five. During Alzheimer’s, there is an accumulation of amyloid-beta plaques and intracellular neurofibrillary tangles within various brain regions. This results in cytotoxicity induced by the amyloid plaques. On the other hand, due to the aggregation of plaques and tangles, there is an activation of microglia cells, specifically by the misfolding of the truncated tau proteins[2]. Microglia cells release specific chemicals to escape through the blood brain barrier and are essential for getting rid of any toxic or pathogenic invaders which are found within the brain. However, it is still controversial if the activation of microglia cells is causing negative effects within the brain. Within neuroimmunological research, evidence has been accumulated to support both, the advantages and disadvantages of microglia activation[9]. Specifically, one of the major receptors responsible for the recruitment of microglia is CCR-2 (CC-chemokine receptor 2)[18]. CCR-2 recruits microglia within the brain to prevent inflammation and can be looked at as a particular target for the treatment of Alzheimer’s disease.[18]

1. Microglial Cells

1.1 Activation of Microglial Cells

Microglial cells are the immune cells of the brain. They consistently survey the brain to look for any abnormalities or any problems that need to be eliminated. During Alzheimer’s disease, microglial cells are activated by the release of toxic substances from the brain and plaques which can cause degeneration of the neuronal cells. However, it has been shown that due to the misfolding of the tau protein, microglial cells are also activated[2]. Norbert Zilka et al. They reproduced transgenic rats which were consisted of mutant tau proteins, in which they discovered that truncated tau protein was stimulating inflammatory responses within the rats. Even though it was found that tau proteins attract microglial cells, it was still unknown at what stage within the tauopathy were the microglial cells being activated[3]. Therefore Shang J et al. studied this idea and determined that during the early stages of tau fibrillary tangles is when the microglial cells are activated due to the over-expression of interleukin-1 (IL-1). Lastly, to prove the relationship between hyper phosphorylation of tau and microglial activation, brain lesions within human and transgenic mice brains were compared[4]. Through the comparison, it was proven that tau neurofibrillary tangles are responsible for the activation of microglial cells by weakening the blood brain barrier.

Advantages of Microglial Function
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Figure 2: Microglial cells releasing growth factors, cleaning up debrises
and repairing neurons to reduce damage within the CNS
Retrieved March 28, 2013 from:

1.2 Advantages of Microglial Activation

Microglial cells represent ten percent of the cells within the CNS. As discussed previously, microglial activation is caused by inflammatory responses due to plaque build-up and neurofibrillary tangles. In 1998, Frautschy S. et al showed that amyloid-beta plaque formation is highly correlated with microglial activation quantitatively. This experiment was able to explain that Alzheimer’s disease also elicits an immunological response[5]. To explain the microglial activation, Wilcock et al. presented a paper where they discovered that the activation of microglial cells took place for the clearance of compacted plaques within the brain. This experiment therefore proved that microglial activation is essential in getting rid of amyloid-beta plaques during Alzheimer’s disease[6].
During Alzheimer’s, there is an over-production of Aβ-42 isoform, which is believed to be responsible for the recruitment of microglial cells. However, Aβ-42 is able to attract bone-marrow derived glial cells which are highly effective in preventing amyloid plaque deposits, rather than peripheral microglial cells[7]. There are many ways to activate microglial cells through the Amyloid-βeta isoforms. However they are not only clearing up amyloid-βeta plaques during Alzheimer’s disease, but also causing a delay in the progression of Alzheimer’s disease. This progression can be specific to cognitive decline[8]. On the other hand, due to the activation of microglial cells, there is also secretion of growth factors and anti-inflammatory cytokines which are proven to be neuroprotective[9]. Similarly, microglial cells are also able to remove damaged cells the CNS to prevent any further damage to the tissues[9].

1.3 Disadvantages of Microglial Activation

Even though microglial activation is considered to be a positive attribute during Alzheimer’s disease, there is also research on the negative consequences of microglial cells activation[10]. These negative aspects have been highly observed within elderly patients, where microglial cells become less efficient and as they become activated from there resting state, they cause further neuronal damage[11]. Specifically, it is due to over-production of pro-inflammatory mediators of microglial cells which are considered cytotoxic[10]. Therefore, due to the increase in neuronal damage, it has been observed that many patients decline in their cognitive abilities[12]. On the other hand, a study conducted by Payao S. et al showed that IL-1 gene polymorphism was playing a relevant part in Alzheimer’s disease pathology. They showed that excessive recruitment of microglial cells was due to the elevated levels of IL-1β[13]. Therefore proving that the gene polymorphism of IL-1 is causing an increase in the susceptible to Alzheimer’s disease

1.4 Controversial Role of Microglial

Within the field of neuroimmunology, there are controversies regarding the activation of microglial cells. It is still difficult to conclude if microglial activation is actually useful or detrimental to the neuronal cells. However, the controversies are more focused towards the particular details. For instance, studies suggest that neurotoxicity associated with Amyloid-βeta depends on the presence of microglia. On the other hand, many scientists believe that the formation of Amyloid-βeta is not dependent on microglia. Thereby a study conducted by Grathwohl et al. where they got rid of all the microglial cells by applying a particular drug and discovered that amyloid plaque formation and maintenance are not associated with the presence of microglia[14]. However, Giulian D et al. found that there amyloid-βeta is consisted of specific domains which help the microglia cells kill neuronal cells[15]. Therefore, both of these studies are contradictory to if amyloid-βeta are or are not dependent on microglia.

2. CCR-2 (CC Chemokine Receptor 2)

2.1 What are CCR-2 Receptors?

CCR-2 (CC Chemokine Receptor 2) also referred to as CD192, is a chemokine receptor, which are particular receptors on cell surface that interact with chemokines. CCR-2 is a G-protein coupled receptor which helps to traffic particular cells to specific locations during an inflammatory response. Therefore it is also specifically responsible for monocyte chemo taxis, helping to recruit microglial cells to inflammatory areas within the brain. It is also believed that CCR-2 is also linked to cognitive functions within the brain[16].

Spatial Memory Water T Maze
Test for CCR Deficiency
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Figure 4: Displays that with CCR2 deficiency, there is increased
cognitive impairment and increase in the time to accomplish the water
T-maze task. Adapted from Naert G. and Rivest S., 2011.

2.2 CCR-2 Deficiency/Knockout

CCR-2 plays a very important role in the immunology of Alzheimer’s disease. To understand the importance of these receptors, it is essential to study the consequences of not having any expressions of CCR-2 within the brain. An experiment conducted by Naert G. and Rivest S. with transgenic mice, CCR2 -/- particularly for Alzheimer’s disease showed increase in cognitive impairments and amyloid pathology. This was due to the inability of being able to recruit microglial cells to the region of inflammation. During the experiment, water T-maze test was utilized to test for hippocampal-dependent spatial memory, in which the CCR-2 deficient performed very poorly in comparison to the control. Also by utilizing tissue analysis and in situ hybridization, it was found that CCR2-/- mice had increase amount of Amyloid-βeta plaques compared to the control[16].
On the other hand, to prove that CCR-2 deficiency impairs microglial cell recruitment, Khoury J. et al. designed an experiment with Alzheimer’s mice models (Tg2576). Through these CCR-2-/- transgenic mice, it was shown that their mortality had declined. Most importantly, it was shown using immunohistochemistry that Amyloid-βeta plaques were highly abundant within the CCR-2 knockout mice than in the control Alzheimer’s disease mice. This proved that without CCR-2, microglial cells cannot be activated and Amyloid-βeta plaques cannot be cleared within the Alzheimer’s disease mice[17]. Therefore, CCR-2 is essential for recruiting microglial cells for the clearance of amyloid-βeta plaques and from preventing cognitive decline within Alzherim’s patients.

Spatial Memory Water T Maze Test
with CCR2 Over-expression
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Figure 5: With CCR2 over-expression , there is increased
cognitive abilities and increase in the ability to complete the
Water T-maze faster. Adapted from Naert G. and Rivest S., 2011.

2.3 CCR-2 Over-expression

Through determining that CCR-2 is important for microglial activation, a treatment approach for Alzheimer’s disease can be found. Consequently, a study done by Naert G. and Rivest S. found that by over-expressing CCR-2 in transgenic mice, a decrease in cognitive impairments and amyloid plaque formation within the Alzheimer’s mice models. By utilizing a virus to insert the CCR-2 gene into the mice for over-expression and observe the behavioural effects through water-t maze and passive avoidance test. Water-T maze was conducted to test the hippocampal –dependent spatial learning. Furthermore, these tests were compared to a normal and a CCR-2-/- knockout mice[18]. Therefore, it was observed that with over-expression of CCR-2, the transgenic mice did much better in the water-T maze and the passive avoidance test than the normal AD mice and CCR-2-/- AD knockout mice. Thereby proving that over-expression of CCR-2 has the ability to prevent cognitive impairment and amyloid plaque accumulation[18]. Further histological evidence was also collected to show the amyloid plaque accumulation quantitatively. After further testing with CCR-2 over-expression, there is potential treatment for Alzheimer’s disease in the near future.
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3. Treatments for Alzheimer’s

3.1 CCR-2 Receptor Antagonists

CCL-2 (chemokine ligand-2) receptors are responsible for recruiting monocytes and many other immune cells to a region of inflammation. CCL2/CCR2 interaction is responsible for the modulation of microglial cell migration. However, it has been observed that during Alzheimer’s disease, there are elevated levels of CCL-2 within the CSF[19]. This means that CCL2 over-expression has detrimental effects during Alzheimer’s as oppose to the CCR-2 overexpression which has positive effects. Therefore it was shown that the elevated levels of CCL-2 are responsible for the increase in cognitive decline observed within Alzheimer’s[20].
CCL-2 interacts with CCR-2 to recruit microglial cells which are responsible for the production of Amyloid-βeta plaques. This is why it was suggested that CCR-2 antagonists are utilized for chronic inflammatory disease treatment for Alzheimer’s patients in the future[21].

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