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1.  Cholesterol and Statins in Alzheimer’s Disease 
Archives of neurology  2011;68(11):1385-1392.
Substantial evidence has accumulated in support of the hypothesis that elevated cholesterol levels increase the risk of developing Alzheimer’s disease (AD). As a result, much work has been done investigating the potential use of lipid-lowering agents (LLAs), particularly statins, as preventive or therapeutic agents for AD. While epidemiology and preclinical statin research (described in Part 1 of this review) have generally supported an adverse role of high cholesterol regarding AD, human studies of statins (reviewed here) show highly variable outcomes, making it difficult to draw firm conclusions. We identify several confounding factors among the human studies, including differing blood-brain barrier permeabilities among statins, the stage in AD at which statins were administered, and the drugs’ pleiotropic metabolic effects, all of which contribute to the substantial variability observed to date. We recommend that future human studies of this important therapeutic topic 1) take the blood-brain barrier permeabilities of statins into account when analyzing results, 2) include specific analyses of effects on low-density and high-density lipoprotein cholesterol, and most importantly, 3) conduct statin treatment trials solely in mild AD patients, who have the best chance for disease modification.
PMCID: PMC3248784  PMID: 22084122
2.  Sporadic hemangioblastomas are characterized by cryptic VHL inactivation 
Hemangioblastomas consist of 10-20% neoplastic “stromal” cells within a vascular tumor cell mass of reactive pericytes, endothelium and lymphocytes. Familial cases of central nervous system hemangioblastoma uniformly result from mutations in the Von Hippel-Lindau (VHL) gene. In contrast, inactivation of VHL has been previously observed in only a minority of sporadic hemangioblastomas, suggesting an alternative genetic etiology. We performed deep-coverage DNA sequencing on 32 sporadic hemangioblastomas (whole exome discovery cohort n = 10, validation n = 22), followed by analysis of clonality, copy number alteration, and somatic mutation. We identified somatic mutation, loss of heterozygosity and/or deletion of VHL in 8 of 10 discovery cohort tumors. VHL inactivating events were ultimately detected in 78% (25/32) of cases. No other gene was significantly mutated. Overall, deep-coverage sequence analysis techniques uncovered VHL alterations within the neoplastic fraction of these tumors at higher frequencies than previously reported. Our findings support the central role of VHL inactivation in the molecular pathogenesis of both familial and sporadic hemangioblastomas.
Electronic supplementary material
The online version of this article (doi:10.1186/s40478-014-0167-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4297409  PMID: 25589003
Central nervous system; Hemangioblastoma; Deep sequencing; Somatic gene alterations; Von Hippel-Lindau gene; Hypoxia-inducible signaling
3.  Cholesterol and Statins in Alzheimer’s Disease 
Archives of neurology  2011;68(10):1239-1244.
Over the past twenty years, evidence has accumulated that high cholesterol levels may increase the risk of developing Alzheimer’s disease (AD). With the global use of statins to treat hypercholesterolemia, this finding has led to the hope that statins could prove useful in treating or preventing AD. However, the results of work on this topic are inconsistent: some studies find beneficial effects, others do not. In this first segment of a two-part review, we examine the complex preclinical and clinical literature on cholesterol and AD. First, we review epidemiological research on cholesterol levels and the risk of AD and discuss the relevance of discrepancies among studies as regards participants’ age and clinical status. Next, we assess studies correlating cholesterol with AD-type neuropathology. The potential molecular mechanisms for cholesterol’s apparent adverse effect on the development of AD are then discussed. Finally, we review preclinical studies of statins and AD. Thus, this first portion of our review provides the background and rationale for investigating statins as potential therapeutic agents in AD patients, the subject of the second part.
PMCID: PMC3211071  PMID: 21987540
4.  Secreted Amyloid β-Proteins in a Cell Culture Model Include N-Terminally Extended Peptides That Impair Synaptic Plasticity 
Biochemistry  2014;53(24):3908-3921.
Evidence for a central role of amyloid β-protein (Aβ) in the genesis of Alzheimer’s disease (AD) has led to advanced human trials of Aβ-lowering agents. The “amyloid hypothesis” of AD postulates deleterious effects of small, soluble forms of Aβ on synaptic form and function. Because selectively targeting synaptotoxic forms of soluble Aβ could be therapeutically advantageous, it is important to understand the full range of soluble Aβ derivatives. We previously described a Chinese hamster ovary (CHO) cell line (7PA2 cells) that stably expresses mutant human amyloid precursor protein (APP). Here, we extend this work by purifying an sodium dodecyl sulfate (SDS)-stable, ∼8 kDa Aβ species from the 7PA2 medium. Mass spectrometry confirmed its identity as a noncovalently bonded Aβ40 homodimer that impaired hippocampal long-term potentiation (LTP) in vivo. We further report the detection of Aβ-containing fragments of APP in the 7PA2 medium that extend N-terminal from Asp1 of Aβ. These N-terminally extended Aβ-containing monomeric fragments are distinct from soluble Aβ oligomers formed from Aβ1-40/42 monomers and are bioactive synaptotoxins secreted by 7PA2 cells. Importantly, decreasing β-secretase processing of APP elevated these alternative synaptotoxic APP fragments. We conclude that certain synaptotoxic Aβ-containing species can arise from APP processing events N-terminal to the classical β-secretase cleavage site.
PMCID: PMC4070750  PMID: 24840308
5.  Complement Component C3 and Complement Receptor Type 3 Contribute to the Phagocytosis and Clearance of Fibrillar Aβ by Microglia 
Glia  2012;60(6):993-1003.
Complement components and their receptors are found within and around Aβ cerebral plaques in Alzheimer’s disease (AD). Microglia defend against pathogens through phagocytosis via complement component C3 and/or engagement of C3 cleavage product iC3b with complement receptor type 3 (CR3, Mac-1). Here we provide direct evidence that C3 and Mac-1 mediate, in part, phagocytosis and clearance of fibrillar amyloid-β (fAβ) by murine microglia in vitro and in vivo. Microglia took up not only synthetic fAβ42 but also amyloid cores from AD patients, transporting them to lysosomes in vitro. Fibrillar Aβ42 uptake was significantly attenuated by the deficiency or knockdown of C3 or Mac-1 and scavenger receptor class A ligands. In addition, C3 or Mac-1 knockdown combined with a scavenger receptor ligand, fucoidan, further attenutated fibrillar Aβ42 uptake by N9 microglia. Fluorescent fibrillar Aβ42 microinjected cortically was significantly higher in C3 and Mac-1 knockout mice compared to wild-type mice 5 days after surgery, indicating reduced clearance in vivo. Together, these results demonstrate that C3 and Mac-1 are involved in phagocytosis and clearance of fAβ by microglia, providing support for a potential beneficial role for microglia and the complement system in AD pathogenesis.
PMCID: PMC3325361  PMID: 22438044
microglia; Aβ; complement component C3; complement receptor type 3; Mac-1; phagocytosis
6.  The presence of sodium dodecyl sulphate-stable Aβ dimers is strongly associated with Alzheimer-type dementia 
Brain  2010;133(5):1328-1341.
The molecular pathways leading to Alzheimer-type dementia are not well understood, but the amyloid β-protein is believed to be centrally involved. The quantity of amyloid β-protein containing plaques does not correlate well with clinical status, suggesting that if amyloid β-protein is pathogenic it involves soluble non-plaque material. Using 43 brains from the Newcastle cohort of the population-representative Medical Research Council Cognitive Function and Ageing Study, we examined the relationship between biochemically distinct forms of amyloid β-protein and the presence of Alzheimer-type dementia. Cortical samples were serially extracted with Tris-buffered saline, Tris-buffered saline containing 1% TX-100 and with 88% formic acid and extracts analysed for amyloid β-protein by immunoprecipitation/western blotting. The cohort was divisible into those with dementia at death with (n = 14) or without (n = 10) significant Alzheimer-type pathology, and those who were not demented (n = 19). Amyloid β-protein monomer in extracts produced using Tris-buffered saline and Tris-buffered saline containing 1% TX-100 were strongly associated with Alzheimer type dementia (P < 0.001) and sodium dodecyl sulphate-stable amyloid β-protein dimer was detected specifically and sensitively in Tris-buffered saline, Tris-buffered saline containing 1% TX-100 and formic acid extracts of Alzheimer brain. Amyloid β-protein monomer in the formic acid fraction closely correlated with diffuse and neuritic plaque burden, but was not specific for dementia. These findings support the hypothesis that soluble amyloid β-protein is a major correlate of dementia associated with Alzheimer-type pathology and is likely to be intimately involved in the pathogenesis of cognitive failure.
PMCID: PMC2859152  PMID: 20403962
Alzheimer’s disease pathology; Alzheimer’s disease; amyloid β-protein; biochemistry; cognitive impairment
7.  Biochemical and immunohistochemical analysis of an Alzheimer’s disease mouse model reveals the presence of multiple cerebral Aβ assembly forms throughout life 
Neurobiology of disease  2009;36(2):293-302.
The amyloid β-protein (Aβ) is believed to play a causal role in Alzheimer’s disease, however, the mechanism by which Aβ mediates its’ effect and the assembly form(s) of Aβ responsible remain unclear. Several APP transgenic mice have been shown to accumulate Aβ and to develop cognitive deficits. We have studied one such model, the J20 mouse. Using an immunoprecipitation/Western blotting technique we find an age-dependent increase in Aβ monomer and SDS-stable dimer. But prior to the earliest detection of Aβ dimers, immunohistochemical analysis revealed an increase in oligomer immunoreactivity that was coincident with reduced hippocampal MAP2 and synaptophysin staining. Moreover, biochemical fractionation and ELISA analysis revealed evidence of TBS and triton-insoluble sedimentable Aβ aggregates at the earliest ages studied. These data demonstrate the presence of multiple assembly forms of Aβ throughout the life of J20 mice and highlight the difficulty in attributing synaptotoxicity to a single Aβ species.
PMCID: PMC2782414  PMID: 19660551
Amyloid β-protein; aggregation; oligomers; amyloid precursor protein; J20 mice; synaptophysin; MAP2
8.  Soluble oligomers of amyloid β-protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake 
Neuron  2009;62(6):788-801.
In Alzheimer's disease (AD), the insidious impairment of declarative memory coincides with the accumulation of extracellular amyloid-β protein (Aβ) and intraneuronal tau aggregates. Dementia severity correlates strongly with decreased synapse density in hippocampus and cortex. Although numerous studies show that soluble Aβ oligomers inhibit hippocampal long-term potentiation, their role in long-term synaptic depression (LTD) remains unclear. Here, we report that soluble Aβ oligomers from several sources (synthetic, cell culture, human brain extracts) facilitated electrically-evoked LTD in the CA1 region. Aβ-enhanced LTD was mediated by mGluR or NMDAR activity, depending on the induction protocol. Both forms of LTD were prevented by an extracellular glutamate scavenger system. Aβ-facilitated LTD was closely mimicked by the action of the glutamate reuptake inhibitor TBOA, including a shared dependence on extracellular calcium levels and activation of PP2B and GSK-3 signaling. In accord, synaptic glutamate uptake was significantly decreased by soluble Aβ. We conclude that soluble Aβ oligomers perturb synaptic plasticity by altering glutamate recycling at the synapse and promoting synapse depression.
PMCID: PMC2702854  PMID: 19555648
10.  Alzheimer's disease: synaptic dysfunction and Aβ 
Synapse loss is an early and invariant feature of Alzheimer's disease (AD) and there is a strong correlation between the extent of synapse loss and the severity of dementia. Accordingly, it has been proposed that synapse loss underlies the memory impairment evident in the early phase of AD and that since plasticity is important for neuronal viability, persistent disruption of plasticity may account for the frank cell loss typical of later phases of the disease. Extensive multi-disciplinary research has implicated the amyloid β-protein (Aβ) in the aetiology of AD and here we review the evidence that non-fibrillar soluble forms of Aβ are mediators of synaptic compromise. We also discuss the possible mechanisms of Aβ synaptotoxicity and potential targets for therapeutic intervention.
PMCID: PMC2788538  PMID: 19930651
11.  Amyloid β-Protein Dimers Isolated Directly from Alzheimer Brains Impair Synaptic Plasticity and Memory 
Nature medicine  2008;14(8):837-842.
Alzheimer’s disease (AD) constitutes a rising threat to public health. Despite extensive research in cellular and animal models, identifying the pathogenic agent present in the human brain and showing that it confers key features of AD have not been achieved. We extracted soluble amyloid β–protein (Aβ) oligomers directly from the cerebral cortex of typical AD subjects. The oligomers potently inhibited long term potentiation (LTP), enhanced long term depression (LTD), and reduced dendritic spine density in normal rodent hippocampus. Soluble Aβ from AD brain also disrupted the memory of a learned behavior in normal rats. These various effects were specifically attributable to Aβ dimers. Mechanistically, metabotropic glutamate receptors (mGluR) were required for LTD enhancement and NMDA receptors (NMDAR) for spine loss. Co-administering antibodies to the Aβ N-terminus prevented the LTP and LTD deficits, whereas antibodies to the mid-region or C-terminus were less effective. Insoluble amyloid plaque cores from AD cortex did not impair LTP unless they were first solubilized to release Aβ dimers, suggesting that plaque cores are largely inactive but sequester Aβ dimers that are synaptotoxic. We conclude that soluble Aβ oligomers extracted from AD brains potently impair synapse structure and function and that dimers are the smallest synaptotoxic species.
PMCID: PMC2772133  PMID: 18568035
12.  Protein Aggregation in the Brain: The Molecular Basis for Alzheimer’s and Parkinson’s Diseases 
Molecular Medicine  2008;14(7-8):451-464.
Developing effective treatments for neurodegenerative diseases is one of the greatest medical challenges of the 21st century. Although many of these clinical entities have been recognized for more than a hundred years, it is only during the past twenty years that the molecular events that precipitate disease have begun to be understood. Protein aggregation is a common feature of many neurodegenerative diseases, and it is assumed that the aggregation process plays a central role in pathogenesis. In this process, one molecule (monomer) of a soluble protein interacts with other monomers of the same protein to form dimers, oligomers, and polymers. Conformation changes in three-dimensional structure of the protein, especially the formation of β-strands, often accompany the process. Eventually, as the size of the aggregates increases, they may precipitate as insoluble amyloid fibrils, in which the structure is stabilized by the β-strands interacting within a β-sheet. In this review, we discuss this theme as it relates to the two most common neurodegenerative conditions—Alzheimer’s and Parkinson’s diseases.
PMCID: PMC2274891  PMID: 18368143

Results 1-12 (12)