J Neurotrauma. 2015 Apr 23. [Epub ahead of print]
ApoE Regulates Injury-Induced Activation of Hippocampal Neural Stem and Progenitor Cells.
Hong S1, Washington P, Kim A, Yang CP, Yu TS, Kernie SG.
Partial recovery from even severe traumatic brain injury (TBI) is ubiquitous and occurs largely through unknown mechanisms. Recent evidence suggests that hippocampal neural stem/progenitor cell (NSPC) activation and subsequent neurogenesis are responsible for at least some aspects of spontaneous recovery following TBI. Apolipoprotein E (ApoE) regulates postnatal neurogenesis in the hippocampus and is therefore a putative mediator of injury-induced neurogenesis. Further, ApoE isoforms in humans are associated with different cognitive outcomes following TBI. To investigate the role of ApoE in injury-induced neurogenesis we exposed wild-type, ApoE-deficient and human ApoE isoform-specific (ApoE3 and ApoE4) transgenic mice crossed with nestin-GFP reporter mice to controlled cortical impact (CCI) and assessed progenitor activation at 2 days post-injury using unbiased stereology. GFP+ progenitor cells were increased by approximately 120% in the ipsilateral hippocampus in injured wild-type mice compared to sham (p
Our results suggest that amyloid burden within the key DMN regions may contribute to local and distant GM atrophy, and that this may explain the cognitive scores.
IMO, European comission has no professional drug experts, they are in COMP when dealing with orphan drugs. But the Comission will sign the documents as president does in the USA. So IMO this is as final as it can get without this last seal.
This paper, now some 3 years old, is still very valid. It is explaining how difficult it is to find a drug to prevent or stop brain degeneration. In this study they tested some 200.000 different compounds and they found that only 8-hydroxyquinols work. To their suprise they found out that PBT2 was already in clinical trials.
So if there is a drug that will work in brain degeneration it is PBT2.
ch, in an AD study we need to know that the patients have AD and so at the moment we need an expensive pet scan to confirm that. Prana wants to have a disease modifying drug and so do everybody else, world needs it. To demonstrate that brain tissue does not disappear when using PBT2, imaging is needed. It will cost a lot to replace Aricept and get 2B in sales but if you have a disease modifying drug, slowing down brain atrophy, you could sell it with 200B in few years with much less work in marketing than now to replace Aricept. Your strategy is different to Prana's. I think they have determined their strategy to demonstrate that PBT2 is a disease modifier. I do not think they will change that, they are so near in demonstrating what is needed. It may be very evident already in the next 2 months.
As you say the Euro study is very indicative, 35% slowing of hippocampus atrophy could get stronger evidence in the extension study ( now only 9% possibility of error) and even the PET-scan result will most likely turn out to be supportive when the role of ApoE will be clear (most likely explaining why only those with high amyloid content had lower SUVR readings after 1 year on PBT2) .
IMO, this kind of a study would be much less expensive than any AD or HD study because there is no need for any expensive imaging. Only general health monitoring and some psychological tests needed. If you cannot get any improvement in 6 months I would say it would not have much value. So a 6 month study with some 50+50 normals could demonstrate the needed efficacy, perhaps with an extension part as in the Imagine study. But there is a need to do a pilot study to estimate how many cases are needed. It could well be that only a 3 month study would be enough because there is not any severe pathology and only some boostering of memory biochemisty is needed. However to get possible new nerves to work, could need more than 3 months.
This is the paper, it free in the net.
Aging Cell. 2014 Apr; 13(2): 351–359.
Published online 2013 Dec 4. doi: 10.1111/acel.12178
A novel approach to rapidly prevent age-related cognitive decline
Paul A Adlard,1,* Amelia Sedjahtera,1 Lydia Gunawan,1 Lisa Bray,1 Dominic Hare,2 Jessica Lear,2 Philip Doble,2 Ashley I Bush,1 David I Finkelstein,1 and Robert A Cherny1,*
kadaicher, I have been wondering why they do not report any hippocampus atrophy results. Most likely there was nothing to report.
ITM, yes ! And in the Xu, Finkelstein, Adlard paper "Interactions of metals and Apolipoprotein E in Alzheimer’s disease" you will find more. All this tells also indirectly why PBT2 can break easier Abeta-apoE4 complex. These patients with abeta-apoE4 complexes have higher SUVR readings and so PBT2 will lower first the SUVRs of these patients.
All of this is related to Zn and Cu affinity of these different apoE molecules with either cystein or arginine residues. Looks like the mechanism of PBT2 has been solved on very basic molecular level when dealing with breaking of amyloid- metal complexes. But PBT2 has many other places where it has demonstrated favorable mechanisms as seen in many mouse studies which cannot be done in humans. But they have given understanding which is now so apparent in the human Imagine study.
Front Aging Neurosci. 2014; 6: 121.
Published online 2014 Jun 12. doi: 10.3389/fnagi.2014.00121
Interactions of metals and Apolipoprotein E in Alzheimer’s disease
He Xu, David I. Finkelstein, and Paul A. Adlard*
We further speculate that metal binding might help to stabilize ApoE in an order of E2 E3 E4 in the proteolytic process, which leads to less ApoE4 and more ApoE4 fragments. This is consistent with the previous findings that APOE4 carriers have less full-length ApoE but more ApoE fragments in brain parenchyma and plasma than APOE2 carriers (Riddell et al., 2008; Gupta et al., 2011); with decreased ApoE levels in APOE4 carriers considered an important factor for AD onset/development (Verghese et al., 2011; Holtzman et al., 2012). Therefore, the stability of ApoE may be affected by metals, and this may help account for the differential effect of the three ApoE alleles on the development of AD.
This was an extract of article "Interactions of metals and Apolipoprotein E in Alzheimer’s disease". It is a free paper and worth reading.
Evidence supporting the link between metals and ApoE
The mechanism by which ApoE4 is associated with AD is still unknown; however, an emerging linkage between metals and ApoE might give a clue. Evidence shows that ApoE isoforms bind to metals such as zinc, copper and iron (that are also involved in the pathogenesis of AD), with the affinity for copper being greater than for iron and zinc (Miyata and Smith, 1996). The precise binding sites for metals on ApoE have yet to be determined, but the four-helix bundle of the N-terminus may allow a coordination of metals (Miyata and Smith, 1996). The metal sequestration properties of ApoE might present metals to Aβ peptides, leading to amyloid deposition or it might account for the antioxidant function of ApoE in AD development. Furthermore, studies support the notion that ApoE2 has the highest affinity for zinc and ApoE4 has the lowest. This is likely a result of structural differences amongst the three isoforms. Cysteine is a strong ligand for zinc, arginine is not (Karlin and Zhu, 1997), so the affinity for zinc is predicted to be greatest for ApoE2 which has cysteine residues at amino acid position 112 and 158 and weakest for ApoE4 which lacks cysteine residues. This likelihood is supported by the results showing that ApoE protects Aβ from zinc-induced precipitation in the order of ApoE2 ApoE3 ApoE4 (Moir et al., 1999). It is also speculated that ApoE4 has a reduced copper binding capacity because of its lack of cysteine residues (Hung et al., 2013). Although direct evidence for the metal:ApoE interaction needs to be demonstrated, these data clearly provide a potentially important avenue of investigation for understanding the mechanism underlying the higher risk of AD in APOE4 carriers. Metal ions, such as zinc, play an essential role in stabilizing protein structures and contributing to protein function (Wang et al., 2010). We further speculate that metal binding might help to stabilize ApoE in an order of E2 E
From the AIBL study: "A decrease in the amount of available plasma ApoE among ε4 allele carriers could have significant implications in the disease process. Given the involvement of ApoE in Aβ clearance and lipid transport, this seems mechanistically plausible. APOE-ε4 carriers have been shown to have increased amyloid burden, and this may be due to decreased clearance from the brain resulting from the limited ApoE available to bind Aβ ,. Looking more closely at the literature regarding brain ApoE levels, this concept has also been demonstrated in targeted replacement mice, in which genotype clearly affected ApoE levels specifically in the CNS (with ε4/ε4 mice having the least brain ApoE ). Also, reduced ApoE plasma and CNS levels correlated with the development of AD, suggesting a direct consequence of having less ApoE. The ApoE4 isoform is reportedly less stable and may be preferentially degraded compared with ApoE3 in astrocytes, providing a possible biological explanation for the decrease in protein availability in this particular genotype .
ApoE isoforms are known to differentially transport and regulate cholesterol levels because of their amino acid differences, with ApoE4 preferentially binding to low-density lipoprotein and ApoE2 or ApoE3 binding to high-density lipoprotein . Cholesterol uptake is also in part dependent upon the ApoE isoform bound to the lipid because ApoE4-mediated cholesterol uptake has been shown to be lower ,. It is likely, therefore, that peripheral ApoE levels, as determined by individual isoforms, have a direct effect on lipid transport and cholesterol levels. APOE-ε4 carriers, having insufficient ApoE, may have reduced distribution of cholesterol to neurons for important functions such as membrane maintenance, repair and synaptogenesis, which are crucial for learning and memory ,,."
Thanks ITM, very important paper. PBT2 or PBT434 or other MPACs will be needed and used in all ischemic vascular dementia cases.
Orphan indications are important, but I am expecting PBT434 to be used also in essential tremor, some 100 million patients have this problem. There are at least some 5 millon parkinson patients in the world and almost 1 million in USA.
ITM, it looks like apoe protein is compeating with PBT2 in protection, the first 6 months they are even but then PBT2 starts winning and the stabilization effect of apoe protein on abeta is not any more enough and PBT2 starts winning. So the protection by Nature is apoe protein but when it is not enough PBT2 is needed. Everything can be much more complex, but this is now my simplification about why it took 6 months before PET scan demonstrated any efficacy in the Imagine study.
One possible explanation:
ACS Chem Biol. 2015 Jan 21. [Epub ahead of print]
Chemical Cross-Linking/Mass Spectrometry Maps the Amyloid β Peptide Binding Region on Both Apolipoprotein E Domains.
Deroo S1, Stengel F, Mohammadi A, Henry N, Hubin E, Krammer EM, Aebersold R, Raussens V.
Apolipoprotein E (apoE) binds the amyloid β peptide (Aβ), one of the major culprits in Alzheimer's disease development. The formation of apoE:Aβ complexes is implicated in both Aβ clearance and fibrillization. However, the binding interface between apoE and Aβ is poorly defined despite substantial previous research efforts, and the exact role of apoE in the pathology of Alzheimer's disease remains largely elusive. Here, we compared the three main isoforms of apoE (E2, E3, and E4) for their interaction with Aβ1-42 in an early stage of aggregation and at near physiological conditions. Using electron microscopy and Western blots, we showed that all three isoforms are able to prevent Aβ fibrillization and form a noncovalent complex, with one molecule of Aβ bound per apoE. Using chemical cross-linking coupled to mass spectrometry, we further examined the interface of interaction between apoE2/3/4 and Aβ. Multiple high-confidence intermolecular apoE2/3/4:Aβ cross-links confirmed that Lys16 is located in the region of Aβ binding to apoE2/3/4. Further, we demonstrated that both N- and C-terminal domains of apoE2/3/4 are interacting with Aβ. The cross-linked sites were mapped onto and evaluated in light of a recent structure of apoE. Our results support binding of the hydrophobic Aβ at the apoE domain-domain interaction interface, which would explain how apoE is able to stabilize Aβ and thereby prevent its subsequent aggregation.
Alzheimers Res Ther. 2015 Feb 20;7(1):16. doi: 10.1186/s13195-015-0105-6. eCollection 2015.
Follow-up plasma apolipoprotein E levels in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL) cohort.
Gupta VB1, Wilson AC1, Burnham S2, Hone E1, Pedrini S1, Laws SM3, Lim WL1, Rembach A4, Rainey-Smith S1, Ames D5, Cobiac L6, Macaulay SL7, Masters CL8, Rowe CC9, Bush AI8, Martins RN10; AIBL Research Group.
Alzheimer's disease (AD) is a growing socioeconomic problem worldwide. Early diagnosis and prevention of this devastating disease have become a research priority. Consequently, the identification of clinically significant and sensitive blood biomarkers for its early detection is very important. Apolipoprotein E (APOE) is a well-known and established genetic risk factor for late-onset AD; however, the impact of the protein level on AD risk is unclear. We assessed the utility of plasma ApoE protein as a potential biomarker of AD in the large, well-characterised Australian Imaging, Biomarkers and Lifestyle Study of Ageing (AIBL) cohort.
Total plasma ApoE levels were measured at 18-month follow-up using a commercial bead-based enzyme-linked immunosorbent assay: the Luminex xMAP human apolipoprotein kit. ApoE levels were then analysed between clinical classifications (healthy controls, mild cognitive impairment (MCI) and AD) and correlated with the data available from the AIBL cohort, including but not limited to APOE genotype and cerebral amyloid burden.
A significant decrease in ApoE levels was found in the AD group compared with the healthy controls. These results validate previously published ApoE protein levels at baseline obtained using different methodology. ApoE protein levels were also significantly affected, depending on APOE genotypes, with ε2/ε2 having the highest protein levels and ε4/ε4 having the lowest. Plasma ApoE levels were significantly
This paper Feb 2015 is free and good to read ( Follow-up plasma apolipoprotein E levels in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL) cohort). The picture No 4 looks familiar because it looks like the picture No 20 in Masters' July 17 presentation. The former the slope indicates ApoE content of AIBL population when SUVR increases and in the latter 1y effect of PBT2 on SUVR (= Abeta burden) at different levels of SUVR.
If these pictures relate to each others at all, it could mean that The effect on SUVR by PBT2 happens more easily when there is less APOE protein in the plasma. This only speculation.
canadian.... They measured also glucose consumption in the Imagine study, no statistical difference, however ( as was the case with cognition). This study below gives some more info about memory and memory deficits : structure- function- cognition.
Cereb Cortex. 2015 Apr 2. pii: bhv062. [Epub ahead of print]
Cognitive Correlates of Basal Forebrain Atrophy and Associated Cortical Hypometabolism in Mild Cognitive Impairment.
Grothe MJ1, Heinsen H2, Amaro E Jr3, Grinberg LT4, Teipel SJ5; Alzheimer's Disease Neuroimaging Initiative.