Cerebral blood volume alterations in the perilesional areas in the rat brain after traumatic brain injury--comparison with behavioral outcome.

In the traumatic brain injury (TBI) the initial impact causes both primary injury, and launches secondary injury cascades. One consequence, and a factor that may contribute to these secondary changes and functional outcome, is altered hemodynamics. The relative cerebral blood volume (CBV) changes in rat brain after severe controlled cortical impact injury were characterized to assess their interrelations with motor function impairment. Magnetic resonance imaging (MRI) was performed 1, 2, 4 h, and 1, 2, 3, 4, 7, and 14 days after TBI to quantify CBV and water diffusion. Neuroscore test was conducted before, and 2, 7, and 14 days after the TBI. We found distinct temporal profile of CBV in the perilesional area, hippocampus, and in the primary lesion. In all regions, the first response was drop of CBV. Perifocal CBV was reduced for over 4 days thereafter gradually recovering. After the initial drop, the hippocampal CBV was increased for 2 weeks. Neuroscore demonstrated severely impaired motor functions 2 days after injury (33% decrease), which then slowly recovered in 2 weeks. This recovery parallelled the recovery of perifocal CBV. CBV MRI can detect cerebrovascular pathophysiology after TBI in the vulnerable perilesional area, which seems to potentially associate with time course of sensory-motor deficit.

Cortical neuronal and glial pathology in TgTauP301L transgenic mice: neuronal degeneration, memory disturbance, and phenotypic variation.

Recapitulation of tau pathologies in an animal model has been a long-standing goal in neurodegenerative disease research. We generated transgenic (TgTauP301L) mice expressing a frontotemporal dementia with parkinsonism linked to chromosome 17 (FTPD-17) mutation within the longest form of tau (2N, 4R). TgTauP301L mice developed florid pathology including neuronal pretangles, numerous Gallyas-Braak-positive neurofibrillary tangles, and glial fibrillary tangles in the frontotemporal areas of the cerebrum, in the brainstem, and to a lesser extent in the spinal cord. These features were accompanied by gliosis, neuronal loss, and cerebral atrophy. Accumulated tau was hyperphosphorylated, conformationally changed, ubiquitinated, and sarkosyl-insoluble, with electron microscopy demonstrating wavy filaments. Aged TgTauP301L mice exhibited impairment in hippocampally dependent and independent behavioral paradigms, with impairments closely related to the presence of tau pathologies and levels of insoluble tau protein. We conclude that TgTauP301L mice recreate the substantial phenotypic variation and spectrum of pathologies seen in FTDP-17 patients. Identification of genetic and/or environmental factors modifying the tau phenotype in these mice may shed light on factors modulating human tauopathies. These transgenic mice may aid therapeutic development for FTDP-17 and other diseases featuring accumulations of four-repeat tau, such as Alzheimer's disease, corticobasal degeneration, and progressive supranuclear palsy.

Cyclohexanehexol inhibitors of Abeta aggregation prevent and reverse Alzheimer phenotype in a mouse model.

When given orally to a transgenic mouse model of Alzheimer disease, cyclohexanehexol stereoisomers inhibit aggregation of amyloid beta peptide (Abeta) into high-molecular-weight oligomers in the brain and ameliorate several Alzheimer disease-like phenotypes in these mice, including impaired cognition, altered synaptic physiology, cerebral Abeta pathology and accelerated mortality. These therapeutic effects, which occur regardless of whether the compounds are given before or well after the onset of the Alzheimer disease-like phenotype, support the idea that the accumulation of Abeta oligomers has a central role in the pathogenesis of Alzheimer disease.

Enhanced sensitivity of dopaminergic neurons to rotenone-induced toxicity with aging.

Rotenone has been reported to induce various degrees of Parkinsonism in rats. We tested whether advancing age alters the sensitivity of dopaminergic neurons to rotenone. A low, systemic dose of rotenone had no effect on young rats, but led to a 20-30% reduction of tyrosine hydroxylase-positive neurons in the substantia nigra of older rats. The effect was specific to nigral dopaminergic neurons and may be associated with the increase of glial cell activation in older rats. These data suggest that age enhances the sensitivity of dopaminergic neurons to rotenone and should be considered when assessing models of Parkinson's disease.

In vivo reduction of amyloid-beta by a mutant copper transporter.

Cu ions have been suggested to enhance the assembly and pathogenic potential of the Alzheimer's disease amyloid-beta (Abeta) peptide. To explore this relationship in vivo, toxic-milk (txJ) mice with a mutant ATPase7b transporter favoring elevated Cu levels were analyzed in combination with the transgenic (Tg) CRND8 amyloid precursor protein mice exhibiting robust Abeta deposition. Unexpectedly, TgCRND8 mice homozygous for the recessive txJ mutation examined at 6 months of age exhibited a reduced number of amyloid plaques and diminished plasma Abeta levels. In addition, homozygosity for txJ increased survival of young TgCRND8 mice and lowered endogenous CNS Abeta at times before detectable increases in Cu in the CNS. These data suggest that the beneficial effect of the txJ mutation on CNS Abeta burden may proceed by a previously undescribed mechanism, likely involving increased clearance of peripheral pools of Abeta peptide.

Comparison of commissural sprouting in the mouse and rat fascia dentata after entorhinal cortex lesion.

Reactive axonal sprouting occurs in the fascia dentata after entorhinal cortex lesion. This sprouting process has been described extensively in the rat, and plasticity-associated molecules have been identified that might be involved in its regulation. To demonstrate causal relationships between these candidate molecules and the axonal reorganization process, it is reasonable to analyze knockout and transgenic animals after entorhinal cortex lesion, and because gene knockouts are primarily generated in mice, it is necessary to characterize the sprouting response after entorhinal cortex lesion in this species. In the present study, Phaseolus vulgaris-leucoagglutinin (PHAL) tracing was used to analyze the commissural projection to the inner molecular layer in mice with longstanding entorhinal lesions. Because the commissural projection to the fascia dentata is neurochemically heterogeneous, PHAL tracing was combined with immunocytochemistry for calretinin, a marker for commissural/associational mossy cell axons. Using both techniques singly as well as in combination (double-immunofluorescence) at the light or electron microscopic level, it could be shown that in response to entorhinal lesion mossy cell axons leave the main commissural fiber plexus, invade the denervated middle molecular layer, and form asymmetric synapses within the denervated zone. Thus, the commissural sprouting response in mice has a considerable translaminar component. This is in contrast to the layer-specific commissural sprouting observed in rats, in which the overwhelming majority of mossy cell axons remain within their home territory. These data demonstrate an important species difference in the commissural/associational sprouting response between rats and mice that needs to be taken into account in future studies.

Mouse models of Alzheimer's disease: the long and filamentous road.

Alzheimer's disease (AD) is characterized by memory impairment leading to dementia, deposition of amyloid plaques and neurofibrillary tangles (NFTs), and neuronal loss. The major component of plaques is the amyloid beta peptide, A beta, whereas NFTs contain hyperphosphorylated forms of the microtubule-associated protein tau (tau). Familial AD (FAD) mutations either elevate A beta synthesis by favoring 'secretase' of the Alzheimer beta-amyloid precursor protein (APP) or enhance the fibrillogenic properties of this peptide. Mutations in the tau gene cause a different disease denoted FTPD-17, but suggest that the aberrant forms of tau seen in AD are unlikely to be benign. These findings imply a complex pathogenic cascade in AD and important goals of transgenic modeling are to capture and stratify this pathogenic process. Several laboratories have created APP transgenic (Tg) mice that exhibit AD-like amyloid pathology and A beta burdens. These Tg lines also exhibit deficits in spatial reference and/or working memory, with immunization against A beta attenuating both AD-associated phenotypes. Tangle-like pathologies are observed in mice expressing FTPD-17 mutant forms of tau, but florid tau pathologies based upon the wild type (wt) tau isoforms present in AD have proven more elusive. Creation of animal models with robust amyloid and tau pathologies, yet free of irrelevant confounding pathologies, remains a major objective in this field.

Cholinergic changes in the APP23 transgenic mouse model of cerebral amyloidosis.

Alzheimer's Disease (AD) is a neurodegenerative disorder that is characterized by extracellular deposits of amyloid-beta peptide (Abeta) and a severe depletion of the cholinergic system, although the relationship between these two events is poorly understood. In the neocortex, there is a loss of cholinergic fibers and receptors and a decrease of both choline acetyltransferase (ChAT) and acetylcholinesterase enzyme activities. The nucleus basalis of Meynert (NBM), which provides the major cholinergic input to the neocortex, undergoes profound neuron loss in AD. In the present study, we have examined the cholinergic alterations in amyloid precursor protein transgenic mice (APP23), a mouse model of cerebral beta-amyloidosis. In aged APP23 mice, our results reveal modest decreases in cortical cholinergic enzyme activity compared with age-matched wild-type mice. Total cholinergic fiber length was more severely affected, with 29 and 35% decreases in the neocortex of aged APP23 mice compared with age-matched wild-type mice and young transgenic mice, respectively. However, there was no loss of cholinergic basal forebrain neurons in these aged APP23 mice, suggesting that the cortical cholinergic deficit in APP23 mice is locally induced by the deposition of amyloid and is not caused by a loss of cholinergic basal forebrain neurons. To study the impact of cholinergic basal forebrain degeneration on cortical amyloid deposition, we performed unilateral NBM lesions in adult APP23 mice. Three to 8 months after lesioning, a 38% reduction in ChAT activity and significant cholinergic fiber loss were observed in the ipsilateral frontal cortex. There was a 19% decrease in Abeta levels of the ipsilateral compared with contralateral frontal cortex with no change in the ratio of Abeta40 to Abeta42. We conclude that the severe cholinergic deficit in AD is caused by both the loss of cholinergic basal forebrain neurons and locally by cerebral amyloidosis in the neocortex. Moreover, our results suggest that disruption of the basal cholinergic forebrain system does not promote cerebral amyloidosis in APP23 transgenic mice.