Infantile neuronal ceroid lipofuscinosis (INCL) is caused by deficiency of the lysosomal enzyme, palmitoyl protein thioesterase 1 (PPT1). We have investigated the onset and progression of pathological changes in Ppt1-deficient mice (Ppt1 −/− ) and the development of their seizure phenotype. Surprisingly, cortical atrophy and neuron loss occurred only late in disease progression, but were preceded by localized astrocytosis within individual thalamic nuclei and the progressive loss of thalamic neurons that relay different sensory modalities to the cortex. This thalamic neuron loss occurred first within the visual system and only subsequently in auditory and somatosensory relay nuclei or the inhibitory reticular thalamic nucleus. The loss of granule neurons and GABAergic interneurons followed in each corresponding cortical region, before the onset of seizure activity. These findings provide novel evidence for successive neuron loss within the thalamus and cortex in Ppt1 −/− mice, revealing the thalamus as an important early focus of INCL pathogenesis.

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Juvenile neuronal ceroid lipofuscinosis (JNCL), or Batten disease, is a neurodegenerative disease resulting from a mutation in CLN3, which presents clinically with visual deterioration, seizures, motor impairments, cognitive decline, hallucinations, loss of circadian rhythm, and premature death in the late-twenties to early-thirties. Using a Cln3 null (Cln3−/−) mouse, we report here several deficits in the cerebellum in the absence of Cln3, including cell loss and early onset motor deficits. Surprisingly, early onset glial activation and selective neuronal loss within the mature fastigial pathway of the deep cerebellar nuclei (DCN), a region critical for balance and coordination, are seen in many regions of the Cln3−/− cerebellum. Additionally, there is a loss of Purkinje cells (PC) in regions of robust Bergmann glia activation in Cln3−/− mice and human JNCL post-mortem cerebellum. Moreover, the Cln3−/− cerebellum had a mis-regulation in granule cell proliferation and maintenance of PC dendritic arborization and spine density. Overall, this study defines a novel multi-faceted, early-onset cerebellar disruption in the Cln3 null brain, including glial activation, cell loss, and aberrant cell proliferation and differentiation. These early alterations in the maturation of the cerebellum could underlie some of the motor deficits and pathological changes seen in JNCL patients.

Mice with the K644E kinase domain mutation in fibroblast growth factor receptor 3 (Fgfr3) (EIIa;Fgfr3(+/K644E)) exhibited a marked enlargement of the brain. The brain size was increased as early as E11.5, not secondary to the possible effect of Fgfr3 activity in the skeleton. Furthermore, the mutant brains showed a dramatic increase in cortical thickness, a phenotype opposite to that in FGF2 knockout mice. Despite this increased thickness, cortical layer formation was largely unaffected and no cortical folding was observed during embryonic days 11.5-18.5 (E11.5-E18.5). Measurement of cortical thickness revealed an increase of 38.1% in the EIIa;Fgfr3(+/K644E) mice at E14.5 and the advanced appearance of the cortical plate was frequently observed at this stage. Unbiased stereological analysis revealed that the volume of the ventricular zone (VZ) was increased by more than two fold in the EIIa;Fgfr3(+/K644E) mutants at E14.5. A relatively mild increase in progenitor cell proliferation and a profound decrease in developmental apoptosis during E11.5-E14.5 most likely accounts for the dramatic increase in total telecephalic cell number. Taken together, our data suggest a novel function of Fgfr3 in controlling the development of the cortex, by regulating proliferation and apoptosis of cortical progenitors.

Finnish variant LINCL (vLINCL Fin ) is the result of mutations in the CLN5 gene. To gain insights into the pathological staging of this fatal pediatric disorder, we have undertaken a stereological analysis of the CNS of Cln5 deficient mice (Cln5 -/-) at different stages of disease progression. Consistent with human vLINCL Fin , these Cln5 -/-mice displayed a relatively late onset regional atrophy and generalized cortical thinning and synaptic pathology, preceded by early and localized glial responses within the thalamocortical system. However, in marked contrast to other forms of NCL, neuron loss in Cln5 -/-mice began in the cortex and only subsequently occurred within thalamic relay nuclei. Nevertheless, as in other NCL mouse models, this progressive thalamocortical neuron loss was still most pronounced within the visual system. These data provide unexpected evidence for a distinctive sequence of neuron loss in the thalamocortical system of Cln5 -/-mice, diametrically opposed to that seen in other forms of NCL.

Cellular prion protein (PrPc) is a glycoprotein expressed at low to moderate levels within the nervous system. Recent studies suggest that PrPc may possess neuroprotective functions and that its expression is upregulated in certain neurodegenerative disorders. We investigated whether PrPc expression is altered in the frontal and occipital cortex in two well-characterized neurodegenerative disorders—Alzheimer's disease (AD) and diffuse Lewy body disease (DLBD)—compared with that in normal human brain using immunohistochemistry and computerized image analysis. The distribution of PrPc was further tested for correlation with glial reactivity. We found that PrPc was localized mainly in the gray matter (predominantly in neurons) and expressed at higher levels within the occipital cortex in the normal human brain. Image analysis revealed no significant variability in PrPc expression between DLBD and control cases. However, blood vessels within the white matter of DLBD cases showed immunoreactivity to PrPc. By contrast, this protein was differentially expressed in the frontal and occipital cortex of AD cases; it was markedly overexpressed in the former and significantly reduced in the latter. Epitope specificity of antibodies appeared important when detecting PrPc. The distribution of PrPc did not correlate with glial immunoreactivity. In conclusion, this study supports the proposal that regional changes in expression of PrPc may occur in certain neurodegenerative disorders such as AD, but not in other disorders such as DLBD.

Introduction:  Cellular prion protein (PrPc) is a normal glycosyl phosphatidylinositol‐anchored protein expressed on a wide variety of cell types. Within the CNS, low levels of PrPc are particularly associated with neurons in normal healthy individuals. In contrast, a more pronounced expression of this protein may occur in certain neurodegenerative disorders (Esiri et al. Neuropath Appl Neurobiol 2000; 26: 273; Voigtlander et al. Acta Neuropathol 2001; 101: 417). Overexpression of PrPc has itself been reported to demonstrate neuropathology in transgenic mice (Westaway et al. Cell 1994; 76: 117). The present study investigated whether prion protein is up‐regulated in two well‐characterized neurodegenerative disorders: Alzheimer's disease (AD) and diffuse Lewy body disease (DLBD). Material and methods:  Frozen material (frontal and occipital cortex) from cases with AD (n = 10), DLBD (n = 10) and neuropathologically normal brain (n = 10) were obtained from the MRC Brain Bank (Institute of Psychiatry, London), serially sectioned at 15–20 µm and immunoreacted in entire batches with four antisera to detect PrPc (3f4, sp40, 12f10 and F89/160.1.5) using the DAKO ABC method and DAB as chromogen. Sections from a case with Creutzfeldt‐Jakob disease served as positive controls. Negative controls included preincubating test sections with proteinase K/guanidinium thiocyanate/formic acid, omitting primary antibody or incubation with nonspecific IgG. Immunoreactivity within selected brain regions was analysed using OPTIMAS image analysis software (OPTIMAS Corp., USA) on duplicate sections, and data processed as percentage immunoreactivity per defined field, based on a constant threshold (von Eitzen et al. JNEN 1998; 57: 246). The distribution of PrPc was further tested for correlation with glial reactivity (GFAP, PGM‐1). Results:  PrPc expression was mainly localized to the grey matter and was higher in occipital than frontal cortex. PrPc did not colocalize with glial reactivity. Instead, expression within the grey matter appeared to associate with neurons. Expression did not vary significantly between DLBD and controls. However, regional variations in PrPc expression were noted in AD. Epitope specificity of antibodies was also important in detecting PrPc, and may relate to selective regional glycosylation patterns of this protein. Conclusion:  This study indicates that changes in expression of PrPc occur in certain neurodegenerative disorders such as AD. Whether this is secondary to the disease or contributes towards pathology remains to be investigated.