Yamanaka M, Ishikawa T, Griep A, Axt D, Kummer MP, Heneka MT.
PPARγ/RXRα-induced and CD36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice.
J Neurosci. 2012 Nov 28;32(48):17321-31.
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Microglial phagocytosis was recently discovered to eliminate not only cellular debris (such as amyloid-β), but also particular synapses in an experience-dependent manner in the developing and mature central nervous system, thus proposing an unexpected role for microglia in the neuronal circuit remodeling required for learning and memory (see Tremblay et al., 2010; Paolicelli et al., 2011; Schafer et al., 2012; Tremblay et al., 2012).
In Alzheimer’s disease, synapse loss best correlates with the progressive impairment in learning and memory, even though amyloid-β plaques and neurofibrillary tangles of hyperphosphorylated tau are the most prominent hallmarks. Yamanaka et al. reveal that microglial phagocytosis of amyloid-β induced by PPARγ/RXRα activation improves spatial learning and memory in the APPPS1 mouse model. The PPARγ activator DSP-8658 had similar effects.
Is microglial phagocytosis of amyloid-β specifically targeted by the DSP-8658, or does the drug also influence the phagocytosis of synapses in this model? Importantly, answering this question could provide novel insights into the mechanisms underlying the loss of synapses in relation to the hallmarks of Alzheimer’s disease.
Tremblay MÈ, Lowery RL, Majewska AK.
Microglial interactions with synapses are modulated by visual experience.
PLoS Biol. 2010;8(11):e1000527.
Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, Giustetto M, Ferreira TA, Guiducci E, Dumas L, Ragozzino D, Gross CT.
Synaptic pruning by microglia is necessary for normal brain development.
Science. 2011 Sep 9;333(6048):1456-8.
Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME, Barres BA, Stevens B.
Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner.
Neuron. 2012 May 24;74(4):691-705.
Tremblay MÈ, Zettel ML, Ison JR, Allen PD, Majewska AK.
Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices.
Glia. 2012 Apr;60(4):541-58.
This interesting work from Michael Heneka’s group adds to a growing body of evidence bolstering the potential of PPARγ agonists for the treatment of AD. Even more encouraging, the authors’ PPARγ agonist of choice, DSP-8658, is already in developmental trials for treatment of type 2 diabetes and has shown a favorable safety profile so far. The current authors have gone further, though, by also making a foray into mechanistic biology. Specifically, they have nicely shown that PPARγ stimulation promotes microglial Aβ phagocytosis via the innate immune scavenger receptor, CD36. These beneficial effects on Aβ uptake were further augmented by combined agonism of PPARγ and retinoid X receptors. Finally, treatment of the PSAPP mouse model of accelerated cerebral amyloidosis led to an increase in Aβ phagocytosis by microglia in vivo, mitigation of cerebral amyloidosis, and improvement of cognitive impairment. If this mouse model is representative of the clinical syndrome, then the translational potential of PPARγ agonism is certainly something to be excited about.
Even though they are members of the same drug class and share properties, it is also no surprise that pioglitazone and rosiglitazone have disparate effects, as demonstrated by the Aβ results highlighted in the recent publications from the Heneka and the Dineley groups. In fact, we previously showed that pioglitazone and rosiglitazone target different calcium influx pathways (GluRs and VGCCs, respectively) in hippocampal neurons (Pancani et al., 2009). Further, it is well appreciated that they have different effects and safety profiles in the cardiovascular system. Future studies directly comparing the genomic and/or proteomic targets will help parse out the underlying mechanisms responsible for the differences seen with these two drugs.
The proteomic analysis of rosiglitazone actions in the dentate gyrus presented by Dr. Dineley’s group highlighted the ERK/MAPK pathways as a central target. Their results corroborate our prior microarray analysis of hippocampal genes sensitive to pioglitazone in 3xTg AD mice (Searcy et al., 2012). Gene pathways decreased by chronic pioglitazone treatment included synaptic structure and energy metabolism, as well as some inflammatory processes. Conversely, those increased included cellular assembly and biosynthetic processes. Of note, we also identified female hormone/estrogen and glutamatergic neurotransmission as processes targeted by pioglitazone. These processes are also associated with ERK/MAPK signaling and, importantly, with mechanisms of memory formation and recall. Lending support to Dr. Tremblay’s comment above, our work also showed that synaptic communication (throughput and LTP) was also enhanced by pioglitazone, restoring a phenotype typically seen in younger animals.
Finally, it is encouraging to see the development and promising results with a more brain-permeant PPAR-γ agonist (DSP-865, see Heneka paper). Time will tell if this compound will help unify PPAR-γ agonist mechanisms in the brain. Irrespective, an increase in brain permeability is likely to have an important impact on CNS outcome and may also help reduce peripheral side effects.
Pancani T, Phelps JT, Searcy JL, Kilgore MW, Chen KC, Porter NM, Thibault O.
Distinct modulation of voltage-gated and ligand-gated Ca2+ currents by PPAR-gamma agonists in cultured hippocampal neurons.
J Neurochem. 2009 Jun;109(6):1800-11.
Searcy JL, Phelps JT, Pancani T, Kadish I, Popovic J, Anderson KL, Beckett TL, Murphy MP, Chen KC, Blalock EM, Landfield PW, Porter NM, Thibault O.
Long-term pioglitazone treatment improves learning and attenuates pathological markers in a mouse model of Alzheimer's disease.
J Alzheimers Dis. 2012;30(4):943-61.
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