Brain to plasma concentration ratios of i.v. administered human serum albumin (HSA) in the olfactory bulb, frontal cortex and cerebellum were evaluated in DDD mice of different ages. We measured the brain uptake of serum albumin excluding intravascular content by using a double isotope technique and examined the time course of the brain uptake to evaluate the brain uptake at different time intervals. In young adult mice, the value was significantly higher in the olfactory bulb than in other brain regions 3-24 h after (125)I-HSA injection. It was about 2.3 times higher in the olfactory bulb than in the cerebellum (P < 0.01). The high concentration ratios in the olfactory bulb were observed in all 4-22-month-old mice. Moreover, the ratio in the olfactory bulb 24 h after (125)I-HSA injection was higher in 22-month-old mice than in younger animals. The high uptake of serum albumin in the olfactory bulb suggests that intravascular macromolecules can be transported into the olfactory bulb more easily than in other brain regions with tight endothelium, and the persistence of high uptake during adult life may be associated with age-related morphological changes in the olfactory bulb.

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Age-related changes in barrier function in mouse brain I. Accelerated age-related increase of brain transfer of serum albumin in accelerated senescence prone SAM-P/8 mice with deficits in learning and memory.

The time course of brain accumulation of radiolabelled human serum albumin ((125)I-HSA) injected intravenously and the transfer of (125)I-HSA from blood to brain were evaluated in DDD mice using a double isotope technique. The brain accumulation of (125)I-HSA at 3 and 9 h but not at 24 h postinjection and the brain transfer rates were significantly higher in 22-month-old DDD mice than in 4-month-old ones. The brain transfer rates of (125)I-HSA were measured also in senescence accelerated prone mice (SAM-P/8) with age-related deficits in learning and memory, and in senescence accelerated resistant mice (SAM-R/I) without these deficits. The brain transfer rates were significantly higher in 13-month-old SAM-P/8 and 22-month-old SAM-R/1 than in 3-month-old mice of the same strains, respectively. The mean brain transfer rates in five regions observed in 22-month-old DDD mice, 22-month-old SAM-R/1 and 13-month-old SAM-P/8 increased by 31%, 41% and 51% compared with corresponding values in 3- or 4-month-old mice of the same strains. DDD mice and SAM-R/1 mice with normal characteristics of aging showed similar age-related significant changes in brain transfer rates. Age-related increase in the brain transfer rate was manifested at the youngest age in SAM-P/8 among the three strains examined. These findings show that the transfer of human serum albumin into the mouse brain increases with aging and suggest that the barrier function in the mouse brain against macromolecules changes with aging.

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A novel murine model of aging, Senescence-Accelerated Mouse (SAM).

Senescence-Accelerated Mouse (SAM) has been under development by our research team at Kyoto University since 1970, based on the AKR/J strain donated by the Jackson Laboratory in 1968. The SAM mouse has an accelerated senescence and age-associated pathologies such as senile amyloidosis, senile osteoporosis, degenerative joint disease, cataract, deficits in learning and memory, brain atrophy, hyperinflation of lungs, hearing impairment and so on. SAM research is advancing world-wide and attempts are being made to clarify fundamental mechanisms involved in primary aging processes, pathogenesis of age-associated pathologies and effective methods to modulate or ameliorate the advance of senescence and disease processes involved in age-associated pathologies.

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Effect of aging on NADPH-diaphorase neurons in laterodorsal tegmental nucleus and striatum of mice.

Age-related changes of reduced nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d)-containing neurons were examined quantitatively in the laterodorsal tegmental nucleus (TLD) and the caudate-putamen of mice. Six 2-month-old and six 25- to 30-month-old DDD mice were studied using computer-assisted image analysis. Although no age-related changes in neuronal counts were found in the TLD, the cell size in this nucleus showed a statistically significant reduction with aging. In addition, the degree of the age-related neuronal shrinkage differed within the TLD; the most significant occurring in the rostral, less in the caudal third and no significant alteration being found in the middle third portion of TLD. In contrast, NADPH-d-positive neurons in the striatum did not show distinct age-related changes. NADPH-d-containing neurons in the TLD correspond to cholinergic cells, which project to the forebrain. Thus, the age-related shrinkage of NADPH-d neurons in the TLD may be related to the cholinergic dysfunctions seen in the forebrain of senescent mice.

Aging↗

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Deterioration in learning and memory of fear conditioning in response to context in aged SAMP8 mice.

This study examined age-dependent deficits in the learning and memory of fear conditioning, using a newly developed senescence-accelerated mouse (SAMP8) model of age-related brain dysfunction and its genetically related inbred strain (SAMR1). The mice were classically conditioned to tone by giving aversive foot shocks in a distinct experimental box (context). After conditioning, fear in response to the original context without the tone and to the tone in a different context were tested with no shocks. Freezing behavior was used as a reliable index of fear. At 4 and 8 months, contextual fear was weaker in the accelerated senescence-prone SAMP8 mice than in the accelerated senescence-resistant SAMR1 mice. However, at 1 and 2 months, both SAMP8 and SAMR1 mice showed significant contextual fear to equivalent levels. Aging did not affect the fear response to tone. These results indicate that SAMP8 mice have age-related learning and memory deficits in their fear response evoked by contextual but not explicit tone stimuli. Age-related hippocampal dysfunction is suggested to be the cause of these age-related deficits in contextual fear conditioning in SAMP8 mice.

Aging↗

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Ultrastructural and permeability features of microvessels in the hippocampus, cerebellum and pons of senescence-accelerated mice (SAM).

We previously reported that the accumulation of blood-borne radiolabelled serum albumin in brain parenchyma increased with aging, especially in senescence-accelerated mice (SAMP8), which showed age-related deficits in learning and memory. In this study, in order to examine morphological events related to the age-related increase of the brain accumulation of serum albumin, the transvascular passage of blood-borne horseradish peroxidase (HRP) and ultrastructural features of microvessels were examined in the hippocampus, cerebellum and pons of SAMP8 and SAMR1 (control) mice. Ultrastructural examination of the hippocampus showed that the staining for HRP was occasionally spreading throughout the parajunctional cytoplasm of the endothelial cell of aged SAMP8 mice, but not in young SAMP8 mice nor in SAMR1 mice. The number of vessels showing the staining reaction for HRP in the parajunctional cytoplasm of the endothelial cells in aged SAMP8 mice increased significantly compared with that in the others. Electron microscopic morphometry showed that there were no significant differences among the number of HRP-positive vesicles per unit area of the endothelial cell cytoplasm in young and old mice of both strains. The staining reaction for HRP was not seen in the basal lamina of microvessels and the perivascular neuropil in all mice examined. Perivascular lipofuscin-like granules and collagen deposits, swelling of astroglial perivascular endfeet and perivascular cells containing foamy, lipid-like droplets were frequently found in several brain regions of aged SAMP8 mice. The perivascular cells with a few lipid-like droplets and more electron-homogeneous lysosomes were occasionally seen in SAMR1 and young SAMP8, while the other findings were scarcely observed in SAMR1 and young SAMP8 mice. These findings suggest that the blood-brain barrier to HRP was preserved in microvessels in three brain regions of SAM mice but the blood microvessels showed some age-related ultrastructural alterations in SAMP8 brains. Uncontrolled passage of HRP through the parajunctional cytoplasm of the endothelial cells may partly contribute to the age-related increase of accumulation of serum albumin in SAMP8 brains.

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Neuropathological studies on strains of senescence-accelerated mice (SAM) with age-related deficits in learning and memory.

In a series of inbred Senescence-Accelerated mice (SAM) strains, accelerated-senescence prone SAMP substrains show early onset and rapid advancement of senescence. SAMP8 and SAMP10, in particular, exhibit a significant age-related deterioration in memory and learning for passive and active avoidance tasks with, respectively, a low and high incidence of systemic senile amyloidosis. In the brains of both SAMP8 and SAMP10 strains, we have found numerous morphological alterations. Here we review the changes seen in both neuronal or glial components in SAMP8/P10 brains. They may serve as markers of the neuronal degeneration leading to the deficits in learning and memory.

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Inferior temporal lobe atrophy and APOE genotypes in Alzheimer's disease. X-ray computed tomography, magnetic resonance imaging and Xe-133 SPECT studies.

The apolipoprotein E (APOE) gene epsilon 4 allele is known to be associated with late-onset familial and sporadic Alzheimer's disease (AD). We assessed the possible relationship between APOE genotypes and morphological or functional changes in AD brains by x-ray computed tomography (CT), magnetic resonance imaging (MRI) and Xe-133 single photon emission CT (SPECT). First, we estimated the change in size of the whole brain and total ventricular system by using two x-ray CT indices, the cerebral index (CI) and ventricular index (VI), respectively. Neither CI nor VI differed significantly among APOE genotypes. Then, we focused on the inferior temporal lobe regions by introducing new MRI indices, the inferior temporal index (ITI), temporal horn index (THI) and infero-medial temporal index (IMTI). We found a significant difference in each MRI index among APOE subgroups; ITI and IMTI were lower, while THI was higher in AD patients with at least one APOE epsilon 4 allele (epsilon 4+ group) than in those without such an allele (epsilon 4-group). Finally, we compared relative regional cerebral blood flow (rCBF) of Xe-133 SPECT among the AD subgroups. Relative rCBF in the cerebral cortex, particularly in the temporal lobe, was lower in the epsilon 4+ group than in the epsilon 4- group. These results indicate that possession, and thus expression, of the APOE epsilon 4 allele affects preferentially the inferior temporal lobe, encompassing the hippocampus and amygdala, in AD patients.

Aged↗