The International journal of developmental biology, 1991
The aim of this paper was to offer for the first time a selective and systematic description of t... more The aim of this paper was to offer for the first time a selective and systematic description of the "Zabreb Neuroembryological Collection" of human brains and to illustrate the major results of our research team. Throughout these 16 years of continuous and systematic research, we have applied different techniques for demonstrating the cytoarchitectonics (Nissl staining), neuronal morphology (Golgi impregnation), synaptogenesis (EM analysis), growing pathways (acetylcholinesterase histochemistry) and transmitter-related properties of developing neuronal populations (immunocytochemistry and acetylcholinesterase histochemistry) on several hundred human brains ranging in age from the 5th week post-conception to 90 years. The combination of classical and modern research techniques applied to the constantly growing developmental collection, as well as the continuous evaluation of our data in the light of experimental work in non-human primates, has led to the discovery of an ear...
Sporadic Alzheimer&am... more Sporadic Alzheimer's disease (sAD) is the most common form of dementia. Rats injected intracerebroventricularly with streptozotocin (STZ-icv) develop insulin-resistant brain state and represent a non-transgenic sAD model with a number of AD-like cognitive and neurochemical features. We explored cognitive, structural and ultrastructural changes in the brain of the STZ-icv rat model over a course of 9 months. Cognitive functions were measured in the STZ-icv- (0.3, 1 and 3 mg/kg) and age-matched control rats by passive avoidance test. Structural changes were assessed by Nissl and Bielschowsky silver staining. Immunohistochemistry and electron microscopy analysis were used to detect amyloid β- (Aβ1-42) and hyperphosphorylated tau (AT8) accumulation and ultrastructural changes in the brain. Memory decline was time- (≤3 months/acute, ≥3 months/progressive) and STZ-icv dose-dependent. Morphological changes were manifested as thinning of parietal cortex (≥1 month) and corpus callosum (9 months), and were more pronounced in the 3 mg/kg STZ group. Early neurofibrillary changes (AT8) were detected from 1 month onward in the neocortex, and progressed after 3 months to the hippocampus. Intracellular Aβ1-42 accumulation was found in the neocortex at 3 months following STZ-icv treatment, while diffuse Aβ1-42-positive plaque-like formations were found after 6 months in the neocortex and hippocampus. Ultrastructural changes revealed enlargement of Golgi apparatus, pyknotic nuclei, and time-dependent increase in lysosome size, number, and density. Our data provide a staging of cognitive, structural/ultrastructural, and neuropathological markers in the STZ-icv rat model that in many aspects seems to be generally comparable to stages seen in human sAD.
In order to observe changes owing to aging and Alzheimer's disease (AD) in the volumes of... more In order to observe changes owing to aging and Alzheimer's disease (AD) in the volumes of subdivisions of the hippocampus and the number of neurons of the hippocampal formation, 18 normal brains from subjects who died of nonneurological causes and had no history of long-term illness or dementia (ten of these brains comprised the aged control group) and 13 AD brains were analyzed. An optimized design for sampling, measuring volume by using the Cavalieri principle, and counting the number of neurons by using the optical disector was implemented on 50 microns-thick cresyl-violet sections. The mean total volume of the principal subdivisions of the hippocampal formation (fascia dentata, hilus, CA3-2, CA1, and subiculum) showed a negative correlation with age in normal subjects (r = -0.56, 2P < 0.05), and a 32% mean reduction in the AD group compared with controls (P < 0.001). This finding supports the measurement of the coronal cross-sectional area and the volume of the hippocampal formation in the clinical diagnosis of AD. There was an inverse relationship between the age of normal subjects and the number of neurons in CA1 (r = -0.84, 2P < 0.0001) and subiculum (r = -0.49, 2P < 0.05) but not in other subdivisions. Pronounced AD-related reductions in neuron number were found only in the subiculum and the fascia dentata. Compared with controls, both losses represented 23% of neurons (P < 0.05). These results 1) confirm that AD is a qualitatively different process from normal aging and 2) reveal the regional selectivity of neuron loss within the hippocampal formation in aging and AD, which may be relevant to understanding the mechanisms involved in the neuron loss associated with the two processes.
The International journal of developmental biology, 1991
The aim of this paper was to offer for the first time a selective and systematic description of t... more The aim of this paper was to offer for the first time a selective and systematic description of the "Zabreb Neuroembryological Collection" of human brains and to illustrate the major results of our research team. Throughout these 16 years of continuous and systematic research, we have applied different techniques for demonstrating the cytoarchitectonics (Nissl staining), neuronal morphology (Golgi impregnation), synaptogenesis (EM analysis), growing pathways (acetylcholinesterase histochemistry) and transmitter-related properties of developing neuronal populations (immunocytochemistry and acetylcholinesterase histochemistry) on several hundred human brains ranging in age from the 5th week post-conception to 90 years. The combination of classical and modern research techniques applied to the constantly growing developmental collection, as well as the continuous evaluation of our data in the light of experimental work in non-human primates, has led to the discovery of an ear...
Sporadic Alzheimer&am... more Sporadic Alzheimer's disease (sAD) is the most common form of dementia. Rats injected intracerebroventricularly with streptozotocin (STZ-icv) develop insulin-resistant brain state and represent a non-transgenic sAD model with a number of AD-like cognitive and neurochemical features. We explored cognitive, structural and ultrastructural changes in the brain of the STZ-icv rat model over a course of 9 months. Cognitive functions were measured in the STZ-icv- (0.3, 1 and 3 mg/kg) and age-matched control rats by passive avoidance test. Structural changes were assessed by Nissl and Bielschowsky silver staining. Immunohistochemistry and electron microscopy analysis were used to detect amyloid β- (Aβ1-42) and hyperphosphorylated tau (AT8) accumulation and ultrastructural changes in the brain. Memory decline was time- (≤3 months/acute, ≥3 months/progressive) and STZ-icv dose-dependent. Morphological changes were manifested as thinning of parietal cortex (≥1 month) and corpus callosum (9 months), and were more pronounced in the 3 mg/kg STZ group. Early neurofibrillary changes (AT8) were detected from 1 month onward in the neocortex, and progressed after 3 months to the hippocampus. Intracellular Aβ1-42 accumulation was found in the neocortex at 3 months following STZ-icv treatment, while diffuse Aβ1-42-positive plaque-like formations were found after 6 months in the neocortex and hippocampus. Ultrastructural changes revealed enlargement of Golgi apparatus, pyknotic nuclei, and time-dependent increase in lysosome size, number, and density. Our data provide a staging of cognitive, structural/ultrastructural, and neuropathological markers in the STZ-icv rat model that in many aspects seems to be generally comparable to stages seen in human sAD.
In order to observe changes owing to aging and Alzheimer's disease (AD) in the volumes of... more In order to observe changes owing to aging and Alzheimer's disease (AD) in the volumes of subdivisions of the hippocampus and the number of neurons of the hippocampal formation, 18 normal brains from subjects who died of nonneurological causes and had no history of long-term illness or dementia (ten of these brains comprised the aged control group) and 13 AD brains were analyzed. An optimized design for sampling, measuring volume by using the Cavalieri principle, and counting the number of neurons by using the optical disector was implemented on 50 microns-thick cresyl-violet sections. The mean total volume of the principal subdivisions of the hippocampal formation (fascia dentata, hilus, CA3-2, CA1, and subiculum) showed a negative correlation with age in normal subjects (r = -0.56, 2P < 0.05), and a 32% mean reduction in the AD group compared with controls (P < 0.001). This finding supports the measurement of the coronal cross-sectional area and the volume of the hippocampal formation in the clinical diagnosis of AD. There was an inverse relationship between the age of normal subjects and the number of neurons in CA1 (r = -0.84, 2P < 0.0001) and subiculum (r = -0.49, 2P < 0.05) but not in other subdivisions. Pronounced AD-related reductions in neuron number were found only in the subiculum and the fascia dentata. Compared with controls, both losses represented 23% of neurons (P < 0.05). These results 1) confirm that AD is a qualitatively different process from normal aging and 2) reveal the regional selectivity of neuron loss within the hippocampal formation in aging and AD, which may be relevant to understanding the mechanisms involved in the neuron loss associated with the two processes.
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Papers by Goran Simic