14 May 2004. Stunted dendritic arbors in a subpopulation of hippocampal granule cells are an early sign of Aβ-induced damage, according to a new study of transgenic PDAPP mice in the May 4 PNAS. The authors suggest that this pathology, which pre-dates amyloid deposition, might serve as a useful marker of the efficacy of any future treatments.
Last year, Floyd Bloom and colleagues published an imaging study of early hippocampal volume changes in the PDAPP mouse (see ARF related news story). Bloom is a cofounder of the biotech firm Neurome in La Jolla, California, and the current study was produced in collaboration with Elan Pharmaceuticals, which holds the patent to the PDAPP mouse. In the present article Bloom, first author Chi-Cheng Wu and their colleagues focused on PDAPP mice at 90 days, an age at which their previous study had already found significant hippocampal volume loss, especially in the granule cell (GC) layers of the dentate gyrus (DG) and the molecular layer, into which the GCs spread their dendrites.
Dendritic morphology of dentate granule cell (GC) subtypes bewteen Tg and nTg mice. Note: Superficially located GC (SGC) of Tg mice exhibited a significant reduction in dendritic trees in compraison with that of nTg mice, while no difference was foun in DGC of both groups of mice. Arrows: Dendritic truncations in mid-to-outer molecular layers (MML and OML) of the dentate gyrus. [GCL: granule cell layer; IML: inner molecular layer] Photo Credit: Chi-Cheng Wu et al., Neurome Inc.
The study takes advantage of technologies that would have dazzled Santiago Ramón y Cajal. The grandfather of neurobiology labored with Camillo Golgi's temperamental silver staining techniques in order to produce his exquisite drawings of neurons at the turn of the 20th century. Until recently, the only technique that has made any claim to challenging the Golgi stain is the tricky, labor-intensive process of poking individual cells to inject horseradish peroxidase or fluorescent dyes.
In recent years, a simple new tool has emerged—the gene gun that blasts gold particles encrusted with DNA or RNA into cells. Dyes can also be attached to the gold and thus delivered to large numbers of cells when the helium blast forces the particles through cell membranes. The lipophilic dyes are transported throughout the cell, including into the dendritic arbors.
Wu and colleagues bombarded hippocampal slices with the fluorescent dye DiI, and then reconstructed 3-D images of randomly selected granule cells of the dentate gyrus. (Their methodology is described in a separate article in the May issue of Cerebral Cortex.) Quantitative analysis of the dendritic arbors of these cells showed a 12 percent reduction in total dendritic length in the PDAPP mice relative to control littermates. Several subsets of cells had even greater dendritic reductions—23 percent for cells in the dorsal blade of the DG, and 32 percent for superficial cells in the posterior GC. Among the latter, the dendritic reduction took place in the middle to outer portions of the molecular layer.
The results support the proposition that early changes occur in the hippocampus long before amyloid deposition takes place, at least in familial AD. The authors suggest these changes could form the basis of assays that can be used in testing the effects of proposed drugs in PDAPP mice.—Hakon Heimer.
Wu CC, Chawla F, Games D, Rydel RE, Freedman S, Schenk D, Young WG, Morrison JH, Bloom FE. Selective vulnerability of dentate granule cells prior to amyloid deposition in PDAPP mice: Digital morphometric analyses. Proc Natl Acad Sci U S A. 2004 May 4;101(18):7141-6. Epub 2004 Apr 26. Abstract
Wu CC, Reilly JF, Young WG, Morrison JH, Bloom FE. High-throughput Morphometric Analysis of Individual Neurons. Cereb Cortex. 2004 May;14(5):543-54. Epub 2004 Mar 28. Abstract