Paul D. Coleman

Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease

The distinction between the neurodegenerative changes that accompany normal ageing and those that characterise Alzheimers disease is not clear. The resolution of this issue has important implications for the design of therapeutic and investigative strategies. To this end we have used modern stereological techniques to compare the regional pattern of neuronal cell loss in the hippocampus related to normal ageing to that associated with Alzheimers disease. The loss related to normal ageing was evaluated from estimates of the total number of neurons in each of the major hippocampal subdivisions of 45 normal ageing subjects who ranged in age from 13 to 101 years. The Alzheimers disease related losses were evaluated from similar data obtained from 7 cases of Alzheimers disease and 14 age matched controls. Qualitative differences were observed in the regional patterns of neuronal loss related to normal ageing and Alzheimers disease. The most distinctive Alzheimers disease related neuron loss was seen in the CA1 region of the hippocampus. In the normal ageing group there was almost no neuron loss in this region (final neuron count in the CA1 region: 4.40 x 10(6) neurons for the Alzheimers disease group vs 14.08 x 10(6) neurons in the normal ageing group). It is concluded that the neurodegenerative processes associated with normal ageing and with Alzheimers disease are qualitatively different and that Alzheimers disease is not accelerated by ageing but is a distinct pathological process.

Neurons may live for decades with neurofibrillary tangles

Neurons containing neurofibrillary tangles (NFT) are one of the pathological hallmarks of Alzheimer disease (AD). It is known that this population of neurons express gene products and thus function to some degree, but it is unknown how long these neurons may survive with NFT. It is also thought that the formation of NFT results in the death of neurons. Using quantitative data on neuron loss and NFT formation as a function of disease duration, we have generated a computer program that models both the degeneration of CA1 hippocampal neurons and the formation of NFT in these neurons in AD. Modeling various neuron survival times with NFT and altering selected assumptions upon which the models are based, we arrive at the conclusions that 1) CA1 hippocampal neurons survive with NFT for about 20 years, and 2) NFT may not be obligatory for death of CA1 hippocampal neurons in AD.

Gene expression changes in the course of normal brain aging are sexually dimorphic.

Gene expression profiles were assessed in the hippocampus, entorhinal cortex, superior-frontal gyrus, and postcentral gyrus across the lifespan of 55 cognitively intact individuals aged 20–99 years. Perspectives on global gene changes that are associated with brain aging emerged, revealing two overarching concepts. First, different regions of the forebrain exhibited substantially different gene profile changes with age. For example, comparing equally powered groups, 5,029 probe sets were significantly altered with age in the superior-frontal gyrus, compared with 1,110 in the entorhinal cortex. Prominent change occurred in the sixth to seventh decades across cortical regions, suggesting that this period is a critical transition point in brain aging, particularly in males. Second, clear gender differences in brain aging were evident, suggesting that the brain undergoes sexually dimorphic changes in gene expression not only in development but also in later life. Globally across all brain regions, males showed more gene change than females. Further, Gene Ontology analysis revealed that different categories of genes were predominantly affected in males vs. females. Notably, the male brain was characterized by global decreased catabolic and anabolic capacity with aging, with down-regulated genes heavily enriched in energy production and protein synthesis/transport categories. Increased immune activation was a prominent feature of aging in both sexes, with proportionally greater activation in the female brain. These data open opportunities to explore age-dependent changes in gene expression that set the balance between neurodegeneration and compensatory mechanisms in the brain and suggest that this balance is set differently in males and females, an intriguing idea.

Synaptic slaughter in Alzheimer's disease

Synaptic loss is currently established as the best neurobiological correlate of the cognitive deficits of Alzheimers disease (AD) [Ann. Neurol. 27 (1990) 457; Ann. Neurol. 30 (1991) 572]. We provide evidence that still living neurons lose synapses in AD, in addition to the synapse loss due to death of neurons. We also provide evidence indicating that in addition to loss of synapses, synaptic function is also affected in AD by decrements in transcript species related to synaptic vesicle trafficking.

A focus on the synapse for neuroprotection in Alzheimer disease and other dementias

Synaptic dysfunction and failure are processes that occur early in Alzheimer disease (AD) and are important targets for protective treatments to slow AD progression and preserve cognitive and functional abilities. Synaptic loss is the best current pathologic correlate of cognitive decline, and synaptic dysfunction is evident long before synapses and neurons are lost. Once synaptic function fails, even in the setting of surviving neurons, there may be little chance of effectively interfering with the disease process. This review emphasizes the importance of preserving synaptic structure and function (i.e., “synaptoprotection”) in AD. Such “synaptoprotective” therapy will probably need to be administered at a critical early time point, perhaps years before onset of clinical symptoms.

Neuron numbers and sizes in aging brain: Comparisons of human, monkey, and rodent data

One of the several sources of interest in aging animal brains is their potential as models of the aging human brain. In this review we examine whether neuron numbers and sizes change similarly in aging human, monkey and rodent brain regions which data are available from more than one species. The number of brain regions studied in more than one species is surprisingly limited. Some regions show correspondence in age-related changes between humans and selected animal models (primary visual cortex, CA1 of hippocampus). For the majority of regions the data are conflicting, even within one species (e.g., somatosensory cortex, frontal cortex, cerebellum, cholinergic forebrain areas, locus coeruleus). Although some of the conflicting data may be attributed to procedural differences, particularly when data are expressed as density changes, much must be attributed to real species and/or strain differences in rodents. We conclude that neuron numbers and sizes may show similar age-related changes in human and animal brains only for sharply defined brain regions, animal species and/or strains, and age ranges.

Epigenetic changes in Alzheimer's disease: Decrements in DNA methylation

DNA methylation is a vital component of the epigenetic machinery that orchestrates changes in multiple genes and helps regulate gene expression in all known vertebrates. We evaluated immunoreactivity for two markers of DNA methylation and eight methylation maintenance factors in entorhinal cortex layer II, a region exhibiting substantial Alzheimers disease (AD) pathology in which expression changes have been reported for a wide variety of genes. We show, for the first time, neuronal immunoreactivity for all 10 of the epigenetic markers and factors, with highly significant decrements in AD cases. These decrements were particularly marked in PHF1/PS396 immunoreactive, neurofibrillary tangle-bearing neurons. In addition, two of the DNA methylation maintenance factors, DNMT1 and MBD2, have been reported also to interact with ribosomal RNAs and ribosome synthesis. Consistent with these findings, DNMT1 and MBD2, as well as p66α, exhibited punctate cytoplasmic immunoreactivity that co-localized with the ribosome markers RPL26 and 5.8s rRNA in ND neurons. By contrast, AD neurons generally lacked such staining, and there was a qualitative decrease in RPL26 and 5.8s rRNA immunoreactivity. Collectively, these findings suggest epigenetic dysfunction in AD-vulnerable neurons.

Epigenetic Differences in Cortical Neurons from a Pair of Monozygotic Twins Discordant for Alzheimer's Disease

DNA methylation [1], [2] is capable of modulating coordinate expression of large numbers of genes across many different pathways, and may therefore warrant investigation for their potential role between genes and disease phenotype. In a rare set of monozygotic twins discordant for Alzheimers disease (AD), significantly reduced levels of DNA methylation were observed in temporal neocortex neuronal nuclei of the AD twin. These findings are consistent with the hypothesis that epigenetic mechanisms may mediate at the molecular level the effects of life events on AD risk, and provide, for the first time, a potential explanation for AD discordance despite genetic similarities.

Quantitative evidence for selective dendritic growth in normal human aging but not in senile dementia

Parahippocampal gyrus was sampled from human brains at autopsy to form three groups: adult (n = 5, mean age 51.2 years), normal aged (n = 5, mean age 79.6), and senile dementia (SD) (n = 5, mean age 76.0). Classification as normal aged or senile demented was based on both behavioral and neuropathological criteria. Tissue was processed for Golgi-Cox, cresyl violet, hematoxylin and eosin and Bodian silver stains. Both atrophied and normal dendritic trees were seen in all cases. Dendrites of layer II pyramidal neurons were quantified with a computer-microscope system. Quantitative data showed that normal aged individuals had longer and more branched dendrites than either adult or SD individuals. There was a slight tendency for SD individuals to have shorter, less-branched dendrites than adults. Differences among groups were greater in apical than in basal portions of the dendritic tree. These differences were largely accounted for by the lengthening and branching (apical dendrites) or lengthening only (basal dendrites) of terminal dendritic segments. These data suggest a model in which aging cortex contains both regressing, dying neurons and surviving, growing neurons. In normal aging it is the latter group that predominates. This is the first demonstration of plasticity in the adult human brain.

Interleukin‐1β Induces Prostaglandin G/H Synthase‐2 (Cyclooxygenase‐2) in Primary Murine Astrocyte Cultures

Abstract: Activation of glial cells and the consequent release of cytokines, proteins, and other intercellular signaling molecules is a well‐recognized phenomenon in brain injury and neurodegenerative disease. We and others have previously described an inducible prostaglandin G/H synthase, known as PGHS‐2 or cyclooxygenase‐2, that is up‐regulated in many cell systems by cytokines and growth factors and down‐regulated by glucocorticoid hormones. In cultured mouse astrocytes we observed increased production of prostaglandin E2 (PGE2) after stimulation with either interleukin‐1β (IL‐1β) or the protein kinase C activator phorbol 12‐myristate 13‐acetate (TPA). This increase in PGE2 content was blocked by pretreatment with dexamethasone and correlated with increases in cyclooxygenase activity measured at 4 h. Northern blots revealed concomitant increases in PGHS‐2 mRNA levels that peaked at 2 h and were dependent on the dosage of IL‐1β. Dexamethasone inhibited this induction of PGHS‐2 mRNA by IL‐1β. TPA, basic fibroblast growth factor, and the proinflammatory factors tumor necrosis factor α and lipopolysaccharide, but not interleukin‐6, also stimulated PGHS‐2 mRNA expression. Relative to IL‐1β, the greater increases in PGE2 production and cyclooxygenase activity caused by TPA correlated with a greater induction of PGHS‐2 mRNA. Furthermore, NS‐398, a specific inhibitor of cyclooxygenase‐2, blocked >80% of the cyclooxygenase activity in TPA‐treated astrocytes. These findings indicate that increased expression of PGHS‐2 contributes to prostaglandin production in cultured astrocytes exposed to cytokines and other factors.