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1.  Stereologic estimates of total spinophilin-immunoreactive spine number in area 9 and the CA1 field: relationship with the progression of Alzheimer’s disease 
Neurobiology of aging  2007;29(9):1296-1307.
The loss of presynaptic markers is thought to represent a strong pathologic correlate of cognitive decline in Alzheimer’s disease (AD). Spinophilin is a postsynaptic marker mainly located to the heads of dendritic spines. We assessed total numbers of spinophilin-immunoreactive puncta in the CA1 and CA3 fields of hippocampus and area 9 in 18 elderly individuals with various degrees of cognitive decline. The decrease in spinophilin-immunoreactivity was significantly related to both Braak neurofibrillary tangle (NFT) staging and clinical severity but not Aβ deposition staging. The total number of spinophilin-immunoreactive puncta in CA1 field and area 9 were significantly related to MMSE scores and predicted 23.5% and 61.9% of its variability. The relationship between total number of spinophilin-immunoreactive puncta in CA1 field and MMSE scores did not persist when adjusting for Braak NFT staging. In contrast, the total number of spinophilin-immunoreactive puncta in area 9 was still significantly related to the cognitive outcome explaining an extra 9.6% of MMSE and 25.6% of the Clinical Dementia Rating scores variability. Our data suggest that neocortical dendritic spine loss is an independent parameter to consider in AD clinicopathologic correlations.
PMCID: PMC2569870  PMID: 17420070
Alzheimer’s disease; cognition; synapses; tangles
2.  Association of ApoE and LRP mRNA levels with dementia and AD neuropathology 
Neurobiology of Aging  2011;33(3):628.e1-628.e14.
Inheritance of the ε4 allele of ApoE is the only confirmed and consistently replicated risk factor for late onset AD. ApoE is also a key ligand for LRP, a major neuronal LDL receptor. Despite the considerable converging evidence that implicates ApoE and LRP in the pathogenesis of AD, the precise mechanism by which ApoE and LRP modulate the risk for AD remains elusive. Moreover, studies investigating expression of ApoE and LRP in AD brain have reported variable and contradictory results. To overcome these inconsistencies, we studied the mRNA expression of ApoE and LRP in the postmortem brain of persons who died at different stages of dementia and AD-associated neuropathology relative to controls by qPCR and Western blotting. Clinical dementia rating scores were used as a measure of dementia severity, whereas, Braak neuropathological staging and neuritic plaque density were used as indices of the neuropathological progression of AD. ApoE and LRP mRNA expression was significantly elevated in the postmortem inferior temporal gyrus (area 20) and the hippocampus from individuals with dementia compared to those with intact cognition. In addition to their strong association with the progression of cognitive dysfunction, LRP and ApoE mRNA levels were also positively correlated with increasing neuropathological hallmarks of AD. Additionally, Western blot analysis of ApoE protein expression in the hippocampus showed that the differential expression observed at the transcriptional level is also reflected at the protein level. Given the critical role played by LRP and ApoE in Aβ and cholesterol trafficking, increased expression of LRP and ApoE may not only disrupt cholesterol homeostasis but may also contribute to some of the neurobiological features of AD, including plaque deposition.
PMCID: PMC3234309  PMID: 21676498
3.  Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature 
Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. β-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective for understanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of Aβ plaques and neurofibrillary tangles. Although Aβ plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.
PMCID: PMC3560290  PMID: 22487856
Aging; Alzheimer disease; Amyloid; Dementia; Epidemiology; Neuropathology; MAPT; Neurofibrillary tangles
4.  Increased expression of cholesterol transporter ABCA1 is highly correlated with severity of dementia in AD hippocampus 
Brain research  2010;1318C:167-177.
To gain insight into ATP-binding cassette transporter A1 (ABCA1) function and its potential role in AD pathology, we analyzed the expression of the cholesterol transporter ABCA1 in postmortem hippocampus from persons at different stages of dementia and AD associated neuropathology relative to cognitively intact normal donors by quantitative polymerase chain reaction (qPCR) and Western blot. In this study clinical dementia rating (CDR) scores were used as a measure of dementia severity, whereas, Braak neuropathological staging and neuritic plaque density were used as an index of the neuropathological progression of AD. Correlation analysis showed that ABCA1 mRNA expression was significantly elevated at the earliest recognizable stage of dementia compared to persons with intact cognition. ABCA1 mRNA was also positively correlated with Braak neuropathological stages and neuritic plaque density counts. Additionally, ABCA1 mRNA levels showed robust correlation with dementia severity even after controlling for the confounding contribution of accompanying neuropathological parameters to ABCA1 mRNA expression. Western blot analyses showed that the differential expression observed at the transcriptional level is also reflected at the protein level. Thus, our study provides transcriptional and translational evidence that the expression of ABCA1, a key modulator of cholesterol transport across the plasma membrane, is dysregulated in the AD brain and that this dysregulation is associated with increasing severity of AD, whether measured functionally as dementia severity or neuropathologically as increased neuritic plaque and neurofibrillary tangle density.
PMCID: PMC2826590  PMID: 20079340
Translational neuroscience  2010;1(4):292-299.
There is growing clinical and neuropathologic evidence suggesting that cognitive decline in early Alzheimer’s disease (AD) is aggravated by a synergistic relationship between AD and cerebrovascular disease associated with cardiovascular risk factors such as diabetes and hypertension. Here we used the stereologic “Space Balls” method to investigate the relationships between AD pathology and cardiovascular risk factors in postmortem human brains of patients with hypertension and diabetes in two groups – one consisting of cases with AD diagnosis and one of cases without. Hippocampal CA1 and CA3 microvasculature length density estimates were generated to characterize quantitatively the contribution of cardiovascular risk factors to the severity of neuropathologic changes. Our main finding is that the mean and variance of length density values in the AD group were significantly increased from the non-AD group, regardless of the absence or presence of a cardiovascular risk factor. An additional finding is that in the AD group without a risk factor, dementia severity correlated with amount of length density change in the CA1 field—this correlation did not exist in the AD groups with risk factors. Our findings suggest a role for cardiovascular risk factors in quantifiable change of hippocampal CA1 field microvasculature, as well as suggest a possible role of cardiovascular risk factors in altering microvasculature pathology in the presence of AD.
PMCID: PMC3039302  PMID: 21331351
Stereology; Space Balls; Cardiovascular risk factors; CA1; CA3; Alzheimer’s disease
6.  Increased expression of RXRα in dementia: an early harbinger for the cholesterol dyshomeostasis? 
Cholesterol content of cerebral membranes is tightly regulated by elaborate mechanisms that balance the level of cholesterol synthesis, uptake and efflux. Among the conventional regulatory elements, a recent research focus has been nuclear receptors, a superfamily of ligand-activated transcription factors providing an indispensable regulatory framework in controlling cholesterol metabolism pathway genes. The mechanism of transcriptional regulation by nuclear receptors such as LXRs involves formation of heterodimers with RXRs. LXR/RXR functions as a sensor of cellular cholesterol concentration and mediates cholesterol efflux by inducing the transcription of key cholesterol shuffling vehicles namely, ATP-binding cassette transporter A1 (ABCA1) and ApoE.
In the absence of quantitative data from humans, the relevance of expression of nuclear receptors and their involvement in cerebral cholesterol homeostasis has remained elusive. In this work, new evidence is provided from direct analysis of human postmortem brain gene and protein expression suggesting that RXRα, a key regulator of cholesterol metabolism is differentially expressed in individuals with dementia. Importantly, RXRα expression showed strong association with ABCA1 and ApoE gene expression, particularly in AD vulnerable regions.
These findings suggest that LXR/RXR-induced upregulation of ABCA1 and ApoE levels may be the molecular determinants of cholesterol dyshomeostasis and of the accompanying dementia observed in AD.
PMCID: PMC2949865  PMID: 20843353

Results 1-6 (6)