Lactadherin is a secreted extracellular matrix protein expressed in phagocytes and contributes to the removal of apoptotic cells. We examined lactadherin expression in brain sections of patients with or without Alzheimer's disease and studied its role in the phagocytosis of amyloid ␤-peptide (A␤). Cells involved in Alzheimer's disease, including vascular smooth muscle cells, astrocytes, and microglia, showed a time-related increase in lactadherin production in culture. Quantitative analysis of the level of lactadherin showed a 35% reduction in lactadherin mRNA expression in the brains of patients with Alzheimer's disease (n ‫؍‬ 52) compared with age-matched controls (n ‫؍‬ 58; P ‫؍‬ 0.003). Interestingly, lactadherin protein was detected in the brains of patients with Alzheimer's disease and controls, with low expression in areas rich in senile plaques and marked expression in areas without A␤ deposition. Using surface plasmon resonance, we observed a direct pro-

Astrocytes and one of their products, IL-6, not only support neurons but also mediate inflammation in the brain. Retinoidrelated orphan receptor-␣ (ROR␣) transcription factor has related roles, being neuro-protective and, in peripheral tissues, antiinflammatory. We examined the relation of ROR␣ to astrocytes and IL-6 using normal and ROR␣ loss-of-function mutant mice. We have shown ROR␣ expression in astrocytes and its up-regulation by pro-inflammatory cytokines. We have also demonstrated that ROR␣ directly trans-activates the Il-6 gene. We suggest that this direct control is necessary to maintain IL-6 basal level in the brain and may be a link between the neuro-supportive roles of ROR␣, IL-6, and astrocytes. Furthermore, after inflammatory stimulation, the absence of ROR␣ results in excessive IL-6 up-regulation, indicating that ROR␣ exerts an indirect repression probably via the inhibition of the NF-B signaling. Thus, our findings indicate that ROR␣ is a pluripotent molecular player in constitutive and adaptive astrocyte physiology.inflammation ͉ staggerer ͉ microglia

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The development of the mammalian cerebral cortex involves a series of mechanisms: from patterning, progenitor cell proliferation and differentiation, to neuronal migration. Many factors influence the development of the cerebral cortex to its normal size and neuronal composition. Of these, the mechanisms that influence the proliferation and differentiation of neural progenitor cells are of particular interest, as they may have the greatest consequence on brain size, not only during development but also in evolution. In this context, causative genes of human autosomal recessive primary microcephaly, such as ASPM and MCPH1, are attractive candidates, as many of them show positive selection during primate evolution. MCPH1 causes microcephaly in mice and humans and is involved in a diverse array of molecular functions beyond brain development, including DNA repair and chromosome condensation. Positive selection of MCPH1 in the primate lineage has led to much insight and discussion of its role in brain size evolution. In this review, we will present an overview of MCPH1 from these multiple angles, and whilst its specific role in brain size regulation during development and evolution remain elusive, the pieces of the puzzle will be discussed with the aim of putting together the full picture of this fascinating gene.