Alzheimer 2013 July-5

 

Pilot study of granulocyte-colony stimulating factor for treatment of Alzheimer’s disease.

J Alzheimers Dis. 2012;31(4):843-55.

Sanchez-Ramos J, Cimino C, Avila R, Rowe A, Chen R, Whelan G, Lin X, Cao C, Ashok R.

Department of Neurology, College of Medicine, USF Health Byrd Alzheimer’s Institute, Tampa, FL, USA. jsramos@health.usf.edu

Abstract

Human granulocyte colony-stimulating-factor (G-CSF) is widely used for treatment of neutropenia and to mobilize stem/progenitor cells for bone marrow transplantation. In studies of thousands of healthy donor subjects treated with G-CSF to mobilize stem/progenitor cells, the side-effect profile has been reported to be mild and reversible. In pre-clinical studies, G-CSF was reported to improve spatial learning performance and to markedly reduce amyloid deposition in hippocampus and entorhinal cortex in a murine model of Alzheimer’s disease (AD). The present study investigated the effects of a five day schedule of G-CSF administration on tolerability, safety, and cognition in eight patients with mild to moderate stage AD. A double-blind placebo control, cross-over design was implemented. Treatment with G-CSF did not result in serious adverse events. The most common and expected side effects were transient increases in white blood cell count, myalgias and diffuse aching that improved with non-steroidal anti-inflammatory medications. Of a battery of cognitive tests administered using the CANTAB computerized system, only the mean paired associate learning (PAL total trials adjusted) was significantly improved at the final visit of the study compared to baseline values (p < 0.05). There were no significant differences in amyloid-β1-42 levels in cerebrospinal fluid measured two weeks after G-CSF and two weeks after placebo treatments. In conclusion, administration of G-CSF in a dosage regimen commonly used for bone marrow donors was well tolerated and safe, and provided a signal of positive change in a hippocampal-dependent task of cognitive performance.

PMID: 22751169

 

Potential Mechanisms of Action of G-CSF

G-CSF is known to have direct actions on bone marrow hematopoietic stem cells as well as direct and indirect effects on brain. In our mouse studies, we have observed that the pro-cognitive effects of G-CSF were associated with reduction of amyloid burden and increased microgliosis in hippocampus and entorhinal cortex (1). G-CSF increases the proliferation of blood stem cells and the total level of circulating monocytes as well as total neutrophils. Increased trafficking of mononuclear cells from blood to brain reinforces the microglial population as the monocytes differentiate into new microglia. G-CSF also appears to be an immune modulator by downregulating inflammatory cytokines and upregulating anti-inflammatory cytokines. The pro-cognitive effects of G-CSF may also be mediated by direct actions on neural cells of the CNS. G-CSF interacts with G-CSF receptors expressed on neural progenitor cells of hippocampus to promote neurogenesis. Hippocampal neurogenesis is known to be linked to formation of new memories (temporal encoding of episodic memory). Since decreased cognition in AD correlates strongly with decreased synaptic connectivity, it will be important to determine the extent to which G-CSF promotes neurogenesis and integration of the new neurons into hippocampal circuitry. At an intracellular level, G-CSF is known to decrease apoptotic signaling and in neural stem cells to increase proliferation.

(1) Sanchez-Ramos J, Song S, Sava V, Catlow B, Dickson A, Lin X, Patel N, Mori T, Cao C, Arendash GW. Granulocyte colony stimulating factor decreases brain amyloid burden and reverses cognitive impairment in Alzheimer’s mice Neuroscience 163:55-72, 2009

Sanchez-Ramos Juan-2

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