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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 and phagocytosis of AB.pdfReceptor 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 and I could not find papers that show that . Detrimental effects of EP2-/- has detrimental effects on the brain (only thing I found: 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 paper thinks EP2 could be a potential target for AD treatment.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