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Most of the ideas here are based mostly on this paper: Phagocytic Clearance in Neurodegeneration and the Wikipedia article on microglia. Shinjini is not done reading the said article yet (as of 6/10/14). But she She will also look into some others the are mentioned at the end.

...

  • Microglia already have AB receptors. Maybe we should look into that. (paper: Phagocytic Clearance in Neurodegeneration)
  • Does the fact that microglia take up soluble AB affect us in any way? (Brian's paper, 6/10, Microglia take up soluble AB by macropinocytosis)

One paper (paper: Anti-Aß immunotherapy in Alzheimer's disease; relevance of transgenic mouse studies to clinical trials Anti-Aß immunotherapy in Alzheimer's disease; relevance of.pdf) is showing that infiltration by T-cells ( CD4+ and CD8+) is really bad (associated with meningoencephalitis). Shinjini wonders if infiltration by macrophages has a similar detrimental effect (but she has not found strong evidence to support this, other than that microglia activation is indicated as contributing to AD. Need to look into that.)

 

Papers Shinjini is looking into (as of 6/10/14):

Phagocytic Clearance in Neurodegeneration (Phagocytic clearance in Neurodegeneration (and AD).pdf)

Variant of TREM2 Associated with the Risk of Alzheimer’s Disease (TREM2 variant and WBC as AD risk factor.pdf)

N-APP binds DR6 to cause axon pruning and neuron death via distinct caspases TREM2 variant and WBC as AD risk factor.pdf(DR6 death receptor and N-APP (beta-amyloid cousin) binding.pdf)


6/11/14


Further reading of "Phagocytic Clearance in Neurodegeneration" revealed that AB (which form?) causes an inflammatory response in microglia that is responsible for neurodegeneration, while upregulating anti-inflammatory cytokines could help increase phagocytic activity and reduce neurodegeneration. Could that be an added/alternate approach? How would we test if it is working?

Image Added

Looking into:

 

TGF-β1 promotes microglial amyloid-β clearance and reduces plaque burden in transgenic mice TGF-beta1 promotes microglial AB clearance.pdf

Microglia Lacking E Prostanoid Receptor Subtype 2 Have Enhanced Aβ Phagocytosis yet Lack Aβ-Activated Neurotoxicity Microglia Lacking E Prostanoid Receptor Subtype 2 have enhanced AB phagocytosis.pdf

 

Also need to look into:

 

Do macrophages actually "evolve" into microglia once in the brain or are they different?

Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions microglia from monocytes.pdf
6/12/14
Anti-inflammatory cytokines involved in a LOT of other things apparently. May not be the best approach to mess with them.
Brian was  excited about macrophages/microglia as chassis idea.  Relevant paper: Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions

6/23/14

Microglia Lacking E Prostanoid Receptor Subtype 2 Have Enhanced AB Phagocytosis yet Lack AB-Activated Neurotoxicity
Deletion of the Prostaglandin E2 EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer’s Disease

The papers think EP2 could be a potential target for AD treatment.

EP2 potential target for AD. Knocking out EP2 increases phagocytosis of AB-immunoreactive material (hence, AB) by a LOT, and microglia lacking EP2 do not cause neurodegeneration. EP2 has been associated with other brain disorders. Detrimental effects of EP2-/-: Salt−sensitive hypertension and reduced fertility in mice lacking the prostaglandin EP2 receptor, Neuroprotective Function of the PGE2EP2 Receptor in Cerebral Ischemia.
We could downregulate EP2 in microglia in response to AB (same as we are planning for BACE1 currently). Since they will only be in microglia, the shouldn't cause problems with other cells. The system should shut down without AB signalling.
6/26/14
I found this paper from Nature (Targeting gene-modified hematopoietic cells to the centralnervous system: Use of green fluorescent protein uncovers microglial engraftment) which showed:
mice which had undergone a bone marrow transplant with GFP-expressing bone marrow cells had GFP-expressing microglia in their brains at a substantial level after four months, which means there is a circulating microglial precursor in our blood (Ly6Chi CCR2+, according to another paper). Engraftment increased and was directed to specific areas of the brain if their was some sort of damage to that area of the brain.

Basically, this would solve our delivery problems. However, this paper is from 2001. They used a full body irradiation of their test mice. And according to this paper, published 2007 in Nature (Microglia in the adult brain arise from Ly-6Chi CCR2+ monocytes only under defined host conditions), the recruitment does not happen if the mice's heads are not irradiated. So, the fact that the first paper irradiated the whole body of the mice may negate their results.
Other interesting things, though (from first paper):
IMPORTANT: "The decreased propensity of the MSCV promoter to transcriptional silencing in vivo is of particular relevance in the CNS where gene silencing is pertinent." *red-flag, red-flag!*
Not so important: "Recently, cells derived from bone marrow (BM) were found to enter the brain in adult life to differentiate into microglia, astrocytes and neurons2–4"
Targeting gene-modified hematopoietic cells to the central nervous system: Use of green fluorescent protein uncovers microglial engraftment