Older news items (pre-2010) brought over from the old website

Gene Therapy

Targeting a key enzyme with gene therapy reversed course of Alzheimer's disease in mouse models

A study using genetically engineered mice has reversed the rats' memory loss by silencing a gene that helps produce amyloid plaques. The size and number of plaques were reduced by two-thirds within a month.

Singer, O. et al. 2005. Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model. Nature Neuroscience, 8, 1343-1349.

http://www.eurekalert.org/pub_releases/2005-09/si-tak092005.php

Gene therapy slows cognitive decline in trial

The first human clinical trial of gene therapy for Alzheimer’s, involving 8 volunteers, has found an increase in the brain’s use of glucose — a sign of brain activity — and a significant slowing of the patients’ rate of cognitive decline in the 6 patients who completed the procedure safely.

Tuszynski, M.H. et al. 2005. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nature Medicine, 11(5), 551-555.

http://www.eurekalert.org/pub_releases/2005-04/uoc--acd041805.php

New gene therapy technique

A new technique using gene therapy to deliver nerve growth factor into regions of the brain where neurons are degenerating is being trialed in a two-year study. The technique, which requires neurosurgery to inject the drug precisely where it is required (the basal forebrain), uses a new drug called CERE-110. Extensive studies in several animal models, including primates, have showed that NGF gene delivery to the basal forebrain prevented the death of cholinergic neurons (which undergo severe degeneration and death in Alzheimer's disease patients).

http://www.eurekalert.org/pub_releases/2004-09/rpsl-seg092004.php

Preliminary results promising in Alzheimer's gene therapy trial

A small, preliminary study has had some success in delaying brain cell loss in early Alzheimer’s patients through the surgical placement of genetically modified tissue directly into their brains.

The study was reported on April 27 at the American Academy of Neurology meeting in San Francisco.

http://www.eurekalert.org/pub_releases/2004-04/uoc--pra042204.php

UCSD team performs first surgery in gene therapy protocol for Alzheimer's disease

In a groundbreaking procedure, physicians at the University of California, San Diego (UCSD) School of Medicine have surgically implanted genetically modified tissue into the brain of an Alzheimer's patient. This launches the first phase of an experimental gene therapy protocol for Alzheimer's disease. The therapy delivers a natural molecule called nerve growth factor (NGF) to the dying cells in the brain.
If the protocol is successful, implanted cells could begin to affect brain function in a month or two, but Tuszynski cautions that "it may take several years to test the procedure in a large enough number of patients to determine whether it will be useful therapy." The therapy is not expected to cure Alzheimer's disease, but it may restore some brain cells and alleviate symptoms such as short-term memory loss for several years.

Conner, J. M., Darracq, M. A., Roberts, J., & Tuszynski, M. H. (2001). Nontropic actions of neurotrophins: Subcortical nerve growth factor gene delivery reverses age-related degeneration of primate cortical cholinergic innervation. Proceedings of the National Academy of Sciences, 98(4), 1941–1946. doi:10.1073/pnas.98.4.1941

http://www.eurekalert.org/pub_releases/2001-04/UNKN-Utpf-0904101.php

CSF shunt

Draining toxins from cerebrospinal fluid stabilizes cognitive decline

The ever-slowing capacity to clear the build-up of such toxins as isoprostanes and misfolded proteins that accumulate in the brains of Alzheimer's disease patients causes the death of cells involved in memory and language. A preliminary study has shown that reducing the levels of isoprostanes by draining cerebral spinal fluid can stave off future reductions in cognitive abilities. Cognitive scores in the 8 patients receiving the treatment were stable after one year, while scores in those not receiving the treatment declined 20%. The next phase of the study involves nearly 100 patients.

Praticò, D., Yao, Y., Rokach, J., Mayo, M., Silverberg, G.G. & McGuire, D. 2004. Reduction of brain lipid peroxidation by CSF drainage in Alzheimer’s disease patients. Journal of Alzheimer's Disease, 6(4), 385-389.

http://www.eurekalert.org/pub_releases/2004-08/uopm-dti082004.php

Can Alzheimer's disease be slowed by shunting cerebrospinal fluid?

A pilot study has tested the hypothesis that improving cerebrospinal fluid (CSF) turnover will slow or stop the progression of dementia in people with Alzheimer's disease. CSF shunting for dementia, described in 1969, was largely abandoned due to mixed clinical results and an unacceptably high incidence of adverse events. However recent clinical studies in which CSF shunting was used to treat patients with symptomatic hydrocephalus demonstrated a coincidental lack of cognitive decline in patients who also had Alzheimer's dementia. A pilot study has found Alzheimer's patients who were shunted experienced relative stability while the control group demonstrated a fairly robust decline in cognitive function over the 12 months of the study. A larger, multi-center, controlled clinical trial is now underway.

Silverberg, G.D., Levinthal, E., Sullivan, E.V., Bloch, D.A., Chang, S.D., Leverenz, J., Flitman, S., Winn, R., Marciano, F., Saul, T., Huhn, S., Mayo, M. & McGuire, D. 2002. Assessment of low-flow CSF drainage as a treatment for AD: Results of a randomized pilot study. Neurology, 59, 1139-1145.

http://www.eurekalert.org/pub_releases/2002-10/aaon-cad101502.php

Possible new surgical treatment

An 18-month, double-blind placebo study into a new surgical treatment for Alzheimer’s disease using a device called the COGNIShunt, is being undertaken by neurologists at Emory University. The shunt is designed to drain cerebrospinal fluid (CSF) from the skull and into the abdominal cavity. By reducing the build-up of CSF around the brain, doctors hope this device will help to stabilize the disease. In a pilot study of the COGNIShunt, the device was well tolerated by individuals with mild to moderate Alzheimer’s disease.

http://www.eurekalert.org/pub_releases/2002-03/euhs-esc032102.php

Animal studies

Neurogenesis improved in Alzheimer mice

Studies of adult neurogenesis in genetically engineered mice have revealed two main reasons why amyloid-beta peptides and apolipoprotein E4 impair neurogenesis, and identified drug treatments that can fix it. The findings point to a deficit in GABAergic neurotransmission or an imbalance between GABAergic and glutamatergic neurotransmission as an important contributor to impaired neurogenesis in Alzheimer’s. While stem cell therapy for Alzheimer’s is still a long way off, these findings are a big step toward that goal.

Gang Li et al. 2009. GABAergic Interneuron Dysfunction Impairs Hippocampal Neurogenesis in Adult Apolipoprotein E4 Knockin Mice. Cell Stem Cell, 5 (6), 634-645. Binggui Sun et al. 2009. Imbalance between GABAergic and Glutamatergic Transmission Impairs Adult Neurogenesis in an Animal Model of Alzheimer's Disease. Cell Stem Cell, 5 (6), 624-633.

http://www.eurekalert.org/pub_releases/2009-12/gi-gsi113009.php

Neural stem cells offer potential treatment for Alzheimer's

Genetically engineered mice performed markedly better on memory tests a month after neural stem cells were injected into their Alzheimer-like brains. The stem cells secreted a protein that created more neural connections, improving cognitive function. Surprisingly, only 6% of the stem cells became neurons (most became ‘support cells’: astrocytes and oligodendrocytes). The benefit of stem cells seemed rather to lie in their secretion of BDNF, which encouraged the formation of new synapses. The direct injection of BDNF also had cognitive benefit, but not as much as with the neural stem cells, which provided a more long-term and consistent supply of the protein.

Norton, M.C. et al. 2009. Caregiver–Recipient Closeness and Symptom Progression in Alzheimer Disease. The Cache County Dementia Progression Study. The Journals of Gerontology Series B: Psychological Sciences and Social Sciences, Advance Access published on June 29, 2009. Full text available at http://www.pnas.org/content/106/32/13594.abstract

http://www.eurekalert.org/pub_releases/2009-07/uoc--nsc072009.php

Growth factor protects key brain cells in Alzheimer's models

In a series of cell culture and animal studies, involving genetically engineered mice, rats, and rhesus monkeys, injections of brain-derived neurotrophic factor (BDNF) resulted in significant improvement in brain functioning and on learning and memory tests. The growth factor, important for neurogenesis, is normally produced in the entorhinal cortex, an area damaged early in Alzheimer’s disease.

Nagahara, A.H. et al. 2009. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease. Nature Medicine, 15, 331–337.

http://www.eurekalert.org/pub_releases/2009-02/uoc--gfp020309.php

Inhibitor of amyloid-beta clearing enzyme found

A new way of destroying amyloid-beta proteins has been found. Following previous research showing that the enzyme cathepsin B destroys the protein, scientists have now succeeded in increasing the activity of the enzyme by reducing the activity of the protease inhibitors cystatin C, the enzyme’s natural inhibitor. In mice, this had the effect of improving memory and extending life.

Sun, B. et al. 2008. Cystatin C-Cathepsin B Axis Regulates Amyloid Beta Levels and Associated Neuronal Deficits in an Animal Model of Alzheimer's Disease. Neuron, 60 (2), 247-257.

http://www.eurekalert.org/pub_releases/2008-10/gi-gsf102008.php

New way to target Alzheimer's disease

In a series of studies in transgenic mice, a synthetic peptide designed to block the interaction between apolipoprotein E and amyloid-beta protein reduced the aggregation of toxic amyloid protein in the brain by around 50%. The treated mice showed no memory decline.

Sadowski, M.J. et al. 2006. Blocking the apolipoprotein E/amyloid- interaction as a potential therapeutic approach for Alzheimer's disease. Proceedings of the National Academy of Sciences, 103, 18787-18792. The full text is available at http://www.pnas.org/cgi/content/full/103/49/18787

http://www.eurekalert.org/pub_releases/2006-12/nyum-sda120406.php

Androgen therapy may slow progress of Alzheimer's disease

Recent studies have suggested a link between testosterone loss in men and Alzheimer’s. A new study has now found a correlation between low testosterone and elevated beta-amyloid, providing more support that testosterone depletion in aging men increases the risk of Alzheimer’s. Testosterone belongs to a group of steroid hormones called androgens. The mouse study found that androgen therapy was successful in preventing beta-amyloid accumulation and cognitive decline in castrated mice.

Rosario, E.R. et al. 2006. Androgens Regulate the Development of Neuropathology in a Triple Transgenic Mouse Model of Alzheimer's Disease. Journal of Neuroscience, 26, 13384-13389.

http://www.eurekalert.org/pub_releases/2006-12/sfn-tm121906.php

Insulin receptor stops progression of Alzheimer's

Following previous research suggesting Alzheimer's might be a brain-specific neuroendocrine disorder, or a Type 3 diabetes, a new study has found that stimulation of a receptor in the brain that controls insulin responses prevents several components of neurodegeneration and preserves learning and memory in rats with induced Alzheimer's disease, raising the possibility that patients in the very early stages of Alzheimer’s might be treatable.

de la Monte, S.M. et al. 2006. Therapeutic rescue of neurodegeneration in experimental type 3 diabetes: relevance to Alzheimer’s disease. Journal of Alzheimer's Disease, 10 (1), 89-109.

http://www.eurekalert.org/pub_releases/2006-09/l-irs092106.php

Brain enzyme treatment for Alzheimer's

In a new approach to treating Alzheimer’s, increasing brain levels of ubiquitin C-terminal hydrolase L1 (Uch-L1) — an enzyme that helps neurons rid themselves of excess or aberrant proteins — has restored a great deal of brain activity to mice with Alzheimer's symptoms. The enzyme Uch-L1 is part of a network that controls a memory molecule called CREB, which is inhibited by amyloid beta proteins in people with Alzheimer's. Uch-L1 is found at reduced levels in the Alzheimer's brain. As well as improving memory in genetically engineered mice, treatments that restored Uch-L1 levels corrected deficits in nerve transmission both in brain slices treated with amyloid-beta and in slices taken from transgenic mice.

Gong, B. et al. 2006. Ubiquitin Hydrolase Uch-L1 Rescues B-Amyloid-Induced Decreases in Synaptic Function and Contextual Memory. Cell, 126, 775–788.

http://www.eurekalert.org/pub_releases/2006-08/cp-bet082106.php
http://www.eurekalert.org/pub_releases/2006-08/cumc-crr082206.php

Why chances of Alzheimer's increase with age

Experiments with roundworms have revealed two important proteins that help slow down the accumulation of amyloid-beta. HSF-1 breaks apart amyloid and disposes of it — but aging slows HSF-1, so it can't keep up. DAF-16 helps it out, by clumping extra amyloid together in a way that makes it less toxic. The finding supports recent research indicating amyloid clumps, or plaques, are not the main problem, rather, smaller amyloid tendrils inside cells are. The study also explains why aging increases the likelihood of Alzheimer’s. Most importantly of all, it suggests a new approach to treating Alzheimer’s.

Cohen, E. et al. 2006. Opposing Activities Protect Against Age-Onset Proteotoxicity. Science, 313 (5793), 1604–1610.

http://www.msnbc.msn.com/id/14290153/
http://www.boston.com/news/nation/articles/2006/08/11/scientists_find_natural_alzheimers_controls/

Potential new treatment strategy for Alzheimer's

A study has identified several new compounds that could play a role in preventing or treating Alzheimer's disease and other degenerative conditions of the nervous system. In culture, these compounds bind with a receptor called p75NTR; a receptor that in the body binds neurotrophins. There is some evidence that in Alzheimer's, some of the neurons that die express the p75NTR binding site, indicating they may be dying because neurotrophins are binding to them. Because the new compounds bind with p75NTR in place of neurotrophins, they may provide a means of preventing damage that neurotrophins would otherwise be causing. The compounds were also found to inhibit the death of oligodendrocytes.

Massa, S.M. et al. 2006. Small, Nonpeptide p75NTR Ligands Induce Survival Signaling and Inhibit proNGF-Induced Death. Journal of Neuroscience, 26, 5288-5300.

http://www.eurekalert.org/pub_releases/2006-05/uoc--pnt051706.php

Memory loss in genetically engineered mice reversed

Mice were genetically engineered to develop dementia; the transgene was designed to be able to be turned off. The researchers expected that when the transgene expressing the dementia was turned off, memory loss would stop. Instead, they were surprised to find the loss was reversed; the mice regained their memory. A further surprise occurred when it was found that the neurofibrillary tangles, thought to be one of the causes of dementia, remained, and even increased, suggesting that the tangles are not a cause of dementia.

SantaCruz, K. et al. 2005. Tau Suppression in a Neurodegenerative Mouse Model Improves Memory Function, Science, 309 (5733), 476-481.

http://www.eurekalert.org/pub_releases/2005-07/uom-uom071105.php

Inhibiting Apolipoprotein E possible means of therapeutic intervention

It has been known that the inflammatory protein ApoE can speed the buildup in the brain of amyloid plaques,but the mechanism has not been known. A mouse study found ApoE is responsible for converting harmless amyloid-beta into the toxic fibrous deposits known as filamentous amyloid. This process is needed to damage nerve cells in parts of the brain controlling memory and cognition. Mice with Alzheimer's disease showed memory deficits only when the ApoE gene was present. The study suggests that preventing ApoE from acting upon amyloid-beta may prove to be an effective means of therapeutic intervention.

Costa, D.A., Nilsson, L.N.G., Bales, K.R., Paul, S.M. & Potter, H. 2004. Apolipoprotein E is required for the formation of filamentous amyloid but not for amorphous AB deposition, in an Aâ PP/PS double transgenic mouse model of Alzheimer's disease. Journal of Alzheimer's Disease, 6, 509–514.

Nilsson, L.N.G., Arendash, G.W., Leighty, R.E., Costa, D.A., Garcia, M.F., Cracciola, J.R., Rojiani, A., Wu, X., Bales, K.R., Paul, S.M. & Potter, H. 2004. Cognitive impairment in PDAPP mice depends on ApoE and ACT-catalyzed amyloid. Neurobiology of Aging, 25 (9), 1153-1167.

http://www.eurekalert.org/pub_releases/2004-10/uosf-rur102904.php

Researchers identify brain protein that halts progression of Alzheimer's

Researchers have identified a protein in the brain, "transthyretin," that halts the progression of Alzheimer's disease in human brain tissue by blocking beta-amyloid.

The findings were presented on October 26 at the 34th annual meeting of the Society for Neuroscience in San Diego, Calif.

http://www.eurekalert.org/pub_releases/2004-10/nioe-rib102504.php

Early clinical treatment can halt progression of Alzheimer's disease

A study using genetically engineered mice has provided evidence that early clinical treatment of brain lesions (by injecting anti-beta-amyloid antibodies into the hippocampus) can halt the progression of Alzheimer's disease. The clearance of amyloid plaques led to the clearance of the lesions caused by neurofibrillary tangles. The effect on neurofibrillary tangles only occurs, however, if done at a particular stage of the tangle’s growth — the earlier the treatment begins, therefore, the better the chance of success. The demonstration that early treatment of amyloid plaques stops the progression of Alzheimer’s provides support for the controversial theory that the accumulation of amyloid plaques is the initiating trigger of the disease process.

Oddo, S., Billings, L., Kesslak, P., Cribbs, D.H. & LaFerla, F.M. 2004. Aβ Immunotherapy Leads to Clearance of Early, but Not Late, Hyperphosphorylated Tau Aggregates via the Proteasome. Neuron, 43, 321-332.

http://www.eurekalert.org/pub_releases/2004-08/uoc--ect072804.php

Buildup of amyloid plaques linked to gene inhibition

Examination of genetically engineered mice and of brain tissue from deceased Alzheimer's patients has found that the buildup of amyloid plaques in the brain dramatically inhibits six genes known to be important for the formation of new memories. The finding suggests a new approach to the treatment of Alzheimer’s disease, combining amyloid-lowering treatment with other strategies designed to block the effect of amyloid on these genes.

Dickey, C.A. et al. 2003. Selectively Reduced Expression of Synaptic Plasticity-Related Genes in Amyloid Precursor Protein + Presenilin-1 Transgenic Mice. Journal of Neuroscience, 23, 5219-5226.

http://www.eurekalert.org/pub_releases/2003-06/uosf-sla062503.php

A new approach to slowing the progression of Alzheimer’s

Researchers have discovered the molecules that play a critical role in making the brain think it is under attack from the amyloid plaques characteristic of Alzheimer’s disease. Microglial cells detect beta amyloid plaques and gear up to fight them as foreign invaders. However, for some unknown reason, they don’t follow through on the attack, but remain inflamed. It is this inflammation that causes a lot of the problem. Research has now shown that the microglial cells at least four different receptor proteins to bind to the amyloid. Each one of these receptor proteins act together at the same time to drive the inflammation. This discovery suggests a new approach to treating Alzheimer’s — finding a means to block these receptors.

Bamberger, M.E., Harris, M.E., McDonald, D.R., Husemann, J. & Landreth, G.E. 2003. A Cell Surface Receptor Complex for Fibrillar b-Amyloid Mediates Microglial Activation. Journal of Neuroscience, 23, 2665-2674.

http://www.eurekalert.org/pub_releases/2003-04/cwru-mti042903.php

Gene transfer reduces levels of key Alzheimer's disease protein

An animal study has found that a molecule that naturally degrades of the protein beta-amyloid (the substance in the amyloid plaques indicative of Alzheimer’s) appears to reduce the levels of that protein by nearly 50% when delivered by gene therapy.

Marr, R.A., Rockenstein, E., Mukherjee, A., Kindy, M.S., Hersh, L.B., Gage, F.H., Verma, I.M. & Masliah, E. 2003. Neprilysin Gene Transfer Reduces Human Amyloid Pathology in Transgenic Mice. Journal of Neuroscience, 23, 1992-1996.

http://www.eurekalert.org/pub_releases/2003-03/si-gtr032003.php

Growth factor creates new neurons; may aid treatment of neurological diseases

In a series of studies, a growth factor (BDNF) was introduced into the adult rat brain, and was found to produce new neurons in various brain regions. BDNF is reduced in parts of the brain of those with Huntington’s disease and Alzheimer’s disease. These studies indicate that supplementing the adult brain with BDNF not only supports neurons in those brains, but also induces new neurons from precursor cells.

Pencea, V., Bingaman, K. D., Wiegand, S. J., & Luskin, M. B. (2001). Infusion of Brain-Derived Neurotrophic Factor into the Lateral Ventricle of the Adult Rat Leads to New Neurons in the Parenchyma of the Striatum, Septum, Thalamus, and Hypothalamus. The Journal of Neuroscience, 21(17), 6706–6717. Retrieved from http://www.jneurosci.org/content/21/17/6706

Benraiss, A., Chmielnicki, E., Lerner, K., Roh, D., & Goldman, S. A. (2001). Adenoviral Brain-Derived Neurotrophic Factor Induces Both Neostriatal and Olfactory Neuronal Recruitment from Endogenous Progenitor Cells in the Adult Forebrain. The Journal of Neuroscience, 21(17), 6718–6731. Retrieved from http://www.jneurosci.org/content/21/17/6718

http://www.eurekalert.org/pub_releases/2001-08/sfn-nnm083101.php

Transplanted human neural stem cells improve memory in rats

Laboratory-grown human neural stem cells, the building blocks of the brain, were successfully transplanted for the first time into the brains of aged rats and dramatically improved the animals' cognitive function. The results of the study could lay the foundation for new treatments in diseases such as Alzheimer's and Parkinson's.
Neural cell transplant studies recently suffered a setback when transplanted fetal cells worsened symptoms in Parkinson's patients. However, such fetal cells are already differentiated. Laboratory-grown stem cells are not differentiated, allowing the host brain to take over, dictating where the stem cells should migrate and what types of cells they should become. As a result, the transplanted cells became functionally integrated into the neuronal circuitry of the host animal. Postmortem examination of the rats' brains demonstrated that the transplanted human brain cells had not only differentiated and were thriving in the new environment, but that the rats' own neuronal fibers had grown dramatically in areas associated with spatial memory.

Qu,T, Brannen, C.L., Kim, H.M., & Sugay, K. (n.d.). Human neural stem cells improve cognitive function of aged brain. Retrieved 27 April 2013, from http://journals.lww.com/neuroreport/Fulltext/2001/05080/Human_neural_ste...

http://www.eurekalert.org/pub_releases/2001-04/UoIa-Thns-2304101.php

Older news items (pre-2010) brought over from the old website

Role of fatty acids in Alzheimer's disease

Fatty acids are rapidly taken up by the brain and incorporated into phospholipids, a class of fats that form the membrane or barrier that shields the content of cells from the external environment. Now genetically engineered mice have revealed that there is a striking increase in arachidonic acid and related metabolites in the hippocampus. Removal or reduction of the enzyme that releases this acid prevented memory deficits in the Alzheimer mice. It’s thought that the acid causes too much excitation.

Sanchez-Mejia, R.O. et al. 2008. Phospholipase A2 reduction ameliorates cognitive deficits in a mouse model of Alzheimer's disease. Nature Neuroscience, 11, 1311-1318.

http://www.eurekalert.org/pub_releases/2008-10/gi-gsi101408.php

Support for view of Alzheimer's as form of diabetes

Research in the last few years has raised the possibility that Alzheimer’s memory loss could be due to a third form of diabetes. A new study clarifies the connection between insulin and Alzheimer’s. It seems that the toxic protein ADDL, found in the brains of individuals with Alzheimer’s, removes insulin receptors from nerve cells, rendering those neurons insulin resistant. The findings suggest that some existing drugs now used to treat diabetic patients may be useful for Alzheimer’s treatment.

Zhao,W-Q. et al. 2007. Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB Journal, published online ahead of print August 24.

http://www.eurekalert.org/pub_releases/2007-09/nu-dst092607.php

Link between size of hippocampus and progression to Alzheimer's

A study of 20 older adults with mild cognitive impairment has found that the hippocampus was smaller in those who developed into Alzheimer's during the 3 year period.

Apostolova, L.G. et al. 2006. Conversion of Mild Cognitive Impairment to Alzheimer Disease Predicted by Hippocampal Atrophy Maps. Archives of Neurology, 63, 693-699.

http://www.eurekalert.org/pub_releases/2006-05/uoc--rml050406.php

Post-mortem brain studies reveal features of mild cognitive impairment

Autopsies have revealed that the brains of patients with mild cognitive impairment display pathologic features that appear to place them at an intermediate stage between normal aging and Alzheimer's disease. For instance, the patients had begun developing neurofibrillary tangles, but the number of plaques was similar to that in healthy patients. All patients with mild cognitive impairment had abnormalities in their temporal lobes, which likely caused their cognitive difficulties, and many also had abnormalities in other areas that did not relate to the features of Alzheimer's disease. In a second study, of 34 patients with mild cognitive impairment who had progressed to clinical dementia before their deaths, 24 were diagnosed (post-mortem) with Alzheimer’s, and 10 with other types of dementia. As in the other study, all patients had abnormalities in their temporal lobes.

Petersen, R.C. et al. 2006. Neuropathologic Features of Amnestic Mild Cognitive Impairment. Archives of Neurology, 63, 665-672.

Jicha, G.A. et al. 2006. Neuropathologic Outcome of Mild Cognitive Impairment Following Progression to Clinical Dementia. Archives of Neurology, 63, 674-681.

http://www.eurekalert.org/pub_releases/2006-05/jaaj-pbs050406.php

Neurons can produce apolipoprotein E

Apolipoprotein E has been known to be synthesized in the brain in support cells such as astrocytes, microglia, and ependymal layer cells. Controversial for the last decade has been the question of whether or not neurons can produce apoE. Using a unique mouse model, researchers have now demonstrated that neurons can produce apoE, but only in response to injury to the brain.

Xu, Q. et al. 2006. Profile and Regulation of Apolipoprotein E (ApoE) Expression in the CNS in Mice with Targeting of Green Fluorescent Protein Gene to the ApoE Locus. Journal of Neuroscience, 26, 4985-4994.

http://www.eurekalert.org/pub_releases/2006-05/gi-gsp051006.php

Protein identified as cause of memory loss

Researchers have identified a substance in the brain that is proven to cause memory loss, giving drug developers a target for creating drugs to treat memory loss in people with dementia. The substance is a form of the amyloid-beta protein that is distinct from plaques and has been given the name Ab*56. Ab*56 impairs memory independently of plaques or neuronal loss, and may contribute to cognitive deficits associated with Alzheimer's disease.

Lesné, S. et al. 2006. A specific amyloid-beta protein assembly in the brain impairs memory. Nature, 440, 352-357.

http://www.eurekalert.org/pub_releases/2006-03/uom-uom_1031306.php

Reduced insulin in the brain triggers Alzheimer's degeneration

By depleting insulin and its related proteins in the brain, researchers have replicated the progression of Alzheimer's disease – including plaque deposits, neurofibrillary tangles, impaired cognitive functioning, cell loss and overall brain deterioration – in an experimental animal model. Brain deterioration was not related to the pancreas, raising the possibility that Alzheimer's is a neuroendocrine disorder, or a Type 3 diabetes.

Lester-Coll, N. et al. 2006. Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer’s disease. Journal of Alzheimer’s Disease, 9(1)

http://www.eurekalert.org/pub_releases/2006-03/l-rii031606.php

Pin1 enzyme key in preventing onset of Alzheimer's disease

An enzyme called Pin1, previously shown to prevent the formation of the tangles characteristic of Alzheimer's brains, has now been shown to also play a pivotal role in guarding against the development of the plaques that are also characteristic of Alzheimer's. These findings establish a direct link between amyloid plaques and tau tangles, and provide further evidence that Pin1 (prolyl isomerase) is essential to protect individuals from age-related neurodegeneration.

Pastorino, L. et al. 2006. The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production Nature, 440, 528-534.

http://www.eurekalert.org/pub_releases/2006-03/hms-nrs032006.php

Link between APOE and memory neurotransmitter

A new link in the complex chain of Alzheimer’s development has been found. It’s been found that receptors that bind apolipoprotein E (APOE) and those that bind glutamate are in fact connected, separated only by a small protein. It may be that inefficient or high levels of APOE are clogging these binding sites, preventing glutamate from activating the processes necessary to form memories. It may also be that the APOE4 variant — associated with Alzheimer's — is less efficient at removing lipid debris in the brain than is APOE2 or APOE3.

Hoe, H-S. et al. 2006. Apolipoprotein E Receptor 2 Interactions with the N-Methyl-D-aspartate Receptor. Journal of Biological Chemistry, 281, 3425-3431.

http://www.eurekalert.org/pub_releases/2006-02/gumc-nrr020906.php

Two pathways lead to Alzheimer's disease

Mild cognitive impairment (MCI), a transitional stage between normal cognition and Alzheimer's disease, has been categorized into two sub-types on the basis of differing symptoms. Those with the amnesic subtype (MCI-A) have memory impairments only, while those with the multiple cognitive domain subtype (MCI-MCD) have other types of mild impairments, such as in judgment or language, and mild or no memory loss. Both sub-types progress to Alzheimer's disease at the same rate. A new imaging technique has now revealed that these types do in fact have different pathologies. The hippocampus of patients with MCI-A was not significantly different from that of Alzheimer's patients (who show substantial shrinkage), but the hippocampus of those with MCI-MCD was not significantly different from that of the healthy controls.

Becker, J.T., Davis, S.W., Hayashi, K.M., Meltzer, C.C., Toga, A.W., Lopez, O.L., Thompson, P.M., for the Imaging Methods and Analysis in Geriatrics Research Group. 2006. Three-dimensional Patterns of Hippocampal Atrophy in Mild Cognitive Impairment. Archives of Neurology, 63, 97-101.

http://www.eurekalert.org/pub_releases/2006-01/uopm-tpf010606.php

Key genetic risk for Alzheimer's linked to myelin breakdown

Myelin, the fatty insulation coating the brain's internal wiring, builds up in childhood, and breaks down as we age. Myelin is critical for speedy communication between neurons. A new study supports a growing body of evidence that myelin breakdown is a key contributor to the onset of Alzheimer disease later in life. Moreover, it has also revealed that the severity and rate of myelin breakdown in healthy older individuals is associated with ApoE status. Thus both age, the most important risk factor for Alzheimer disease, and ApoE status, the second-most important risk factor, seem to act through the process of myelin breakdown.

Bartzokis, G., Lu, P.H., Geschwind, D.H., Edwards, N., Mintz, J. & Cummings, J.L. 2006. Apolipoprotein E Genotype and Age-Related Myelin Breakdown in Healthy Individuals: Implications for Cognitive Decline and Dementia. Archives of General Psychiatry, 63, 63-72.

http://www.eurekalert.org/pub_releases/2006-01/uoc--isl122805.php

Study links Alzheimer's and Down’s syndrome

New research suggests the cognitive problems observed in Alzheimer’s are related to defects in the machinery controlling neuronal connections — PAK enzyme signaling pathways. PAK (p21-activated kinase) enzymes form a family that includes two members (PAK1 and PAK3) that play critical roles in learning and memory. Humans with genetic loss of PAK3 have severe mental retardation. The study reveals that both PAK1 and PAK3 are abnormally distributed and reduced in Alzheimer patients, and that beta-amyloid was directly involved in PAK signaling deficits. The finding suggests therapies designed to address the PAK defect could treat cognitive problems in both patient populations.

Zhao, L. et al. 2006. Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease. Nature Neuroscience, 9, 234–242.

http://www.eurekalert.org/pub_releases/2006-01/uoc--sid012506.php

New technique finds higher levels of creatine in Alzheimer’s brains

Creatine is involved in the maintaining the energy balance in the brain, but creatine, being small and very soluble, is difficult to detect. A new study has now succeeded in detecting creatine in situ, in brain tissue, and has found relatively large deposits in the hippocampus of Alzheimer’s brains. The finding suggests an overlooked aspect of energy disturbance in Alzheimer's disease, but further research is needed to understand it.
Gallant, M. et al. 2006. Focally Elevated Creatine Detected in Amyloid Precursor Protein (APP) Transgenic Mice and Alzheimer Disease Brain Tissue. Journal of Biological Chemistry, 281, 5-8.
http://www.eurekalert.org/pub_releases/2005-12/uow-iar122105.php

More light on apoE4 and Alzheimer’s

A mutant form of a protein that transports cholesterol, apolipoprotein E (apoE) has long been recognized as a causative factor for Alzheimer's disease, but exactly how has been unclear. 299 amino acids are associated with apoE4, but new research has now found which of these amino acids are toxic. These toxic fragments all reside in the mitochondria (the “energy powerhouse” of the cell). The finding suggests a new therapeutic approach, involving blocking interaction of apoE4 fragments with the mitochondria.

Ye, S. et al. 2005. Apolipoprotein (apo) E4 enhances amyloid peptide production in cultured neuronal cells: ApoE structure as a potential therapeutic target. Proceedings of the National Academy of Science, 102 (51), 18700-18705.

http://www.eurekalert.org/pub_releases/2005-12/gi-gsl121405.php

p25 only good in small doses

Elevated levels of a key brain regulatory enzyme called Cdk5 and an associated regulatory protein called p25 have been found in the brains of Alzheimer’s patients. A new mouse study has found that switching on p25 in the hippocampus for only two weeks actually enhanced learning and memory compared to normal mice; however mice in which p25 had been switched on for six weeks showed impaired learning and memory. These mice also showed significant brain atrophy and loss of hippocampal neurons. The two-week pulse of p25 did not cause neurodegeneration and had long-lasting effects on enhancing memory. The researchers suggest that p25 might be produced to compensate for the loss of Cdk5 activity during aging, however chronically high levels lead to neuronal cell death. The findings are consistent with several recent studies suggesting that in the development of Alzheimer’s, compensatory mechanisms that initially enhance neuroplasticity eventually become maladaptive when chronically activated.

Fischer, A., Sananbenesi, F., Pang, P.T., Lu, B. & Tsai, L-H. 2005. Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory. Neuron, 48, 825–838.

http://www.eurekalert.org/pub_releases/2005-12/cp-aje120505.php

“Default” brain activity implicated in Alzheimer's disease

Here’s an unexpected finding: imaging of the brains of 764 adults of various ages has revealed that the regions that are active when people are in “default mode” — not concentrating on anything in particular, just musing to yourself — are the same regions that develop plaques in Alzheimer’s. They also found that, when asked to concentrate on a specific task, individuals with Alzheimer’s showed increased activity in these posterior cortical regions, rather than the decreased activity seen in young, healthy adults. The researchers speculate that dementia may in fact be a consequence of normal cognitive function — a possibility that hasn’t heretofore been considered. The findings raise the hope of developing methods to detect precursors of the disease long before it develops.

Buckner, R.L. et al. 2005. Molecular, Structural, and Functional Characterization of Alzheimer's Disease: Evidence for a Relationship between Default Activity, Amyloid, and Memory. Journal of Neuroscience, 25, 7709-7717.

http://www.eurekalert.org/pub_releases/2005-08/hhmi-bai082405.php

How Alzheimer's impacts important brain cell function

Researchers have found that synaptic proteins, proteins involved in brain cell communications, decrease in the brains of Alzheimer's patients compared to healthy brains from people in the same age range. The decrease in the frontal cortex was more severe than in other portions of the brain. They also found synaptic protein levels were even lower in the brains of patients in the early stages of Alzheimer's disease, suggesting that the loss of these proteins happens very early in the disease process. The reduction of synaptic proteins may be caused by mitochondrial dysfunction, a well-documented occurrence in Alzheimer's.

Reddy, P.H., Mani, G., Park, B.S., Jacques, J., Murdoch, G., Whetsell, W.Jr., Kaye, J. & Manczak, M. 2005. Differential loss of synaptic proteins in Alzheimer’s disease: Implications for synaptic dysfunction Journal of Alzheimer's Disease, 7(2),103-117.

http://www.eurekalert.org/pub_releases/2005-04/ohs-ord040605.php

Research clarifies how Alzheimer's medicines work

New research clarifies how cholinesterase inhibitors alleviate mild-to-moderate Alzheimer's. When scientists chemically blocked receptors for an important neurotransmitter called acetylcholine, even healthy young people found it significantly harder to learn and remember – especially in the face of interference. Cholinesterase inhibitors slow the breakdown of acetylcholine. The finding also helps explain why Parkinson's disease, dementia due to multiple strokes, multiple sclerosis and schizophrenia, are all also associated with memory problems — all these conditions, like Alzheimer’s, are associated with lower levels of acetylcholine in the brain.

Atri, A., Norman, K.A., Nicolas, M.M., Cramer, S.C., Hasselmo, M.E., Sherman, S., Kirchhoff, B.A., Greicius, M.D., Breiter, H.C. & Stern, C.E. 2004. Central Cholinergic Receptors Impairs New Learning and Increases Proactive Interference in a Word Paired-Associate Memory Task. Behavioral Neuroscience, 118 (1).

http://www.eurekalert.org/pub_releases/2004-02/apa-rch020904.php

Why diet, hormones, exercise might delay Alzheimer’s

A theory that changes in fat metabolism in the membranes of nerve cells play a role in Alzheimer's has been supported in a recent study. The study found significantly higher levels of ceramide and cholesterol in the middle frontal gyrus of Alzheimer's patients. The researchers suggest that alterations in fats (especially cholesterol and ceramide) may contribute to a "neurodegenerative cascade" that destroys neurons in Alzheimer's, and that the accumulation of ceramide and cholesterol is triggered by the oxidative stress brought on by the presence of the toxic beta amyloid peptide. The study also suggests a reason for why antioxidants such as vitamin E might delay the onset of Alzheimer's: treatment with Vitamin E reduced the levels of ceramide and cholesterol, resulting in a significant decrease in the number of neurons killed by the beta amyloid and oxidative stress.

Cutler, R.G., Kelly, J., Storie, K., Pedersen, W.A., Tammara, A., Hatanpaa, K., Troncoso, J.C. & Mattson, M.P. 2004. Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease. PNAS, 101, 2070-5.

http://www.eurekalert.org/pub_releases/2004-02/aaft-nsm021004.php

Late-life Alzheimer's begins in midlife

A new model of human brain aging identifies midlife breakdown of myelin, a fatty insulation with very high cholesterol content that wraps tightly around axons (part of the neurons) and enables messages to pass along the “wiring” of the brain speedily, as a possible key to the onset of Alzheimer's disease later in life. Imaging studies and examination of brain tissue shows that the brain's wiring develops until middle age and then begins to decline as the breakdown of myelin triggers a destructive domino affect. It is suggested that genetic factors coupled with the brain's own developmental process of increasing cholesterol and iron levels in middle age help degrade the myelin. The complex connections that take the longest to develop and allow humans to think at their highest level are among the first to deteriorate as the brain's myelin breaks down in reverse order of development. The model suggests that the best time to address the inevitability of myelin breakdown is when it begins, in middle age. Possible preventive therapies include cholesterol- and iron-lowering medications, anti-inflammatory medications, diet and exercise programs and possibly hormone replacement therapy designed to prevent menopause rather than simply ease the symptoms. Education and cognitively stimulating activities may also stimulate the production of myelin.

Bartzokis, G. 2003. Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer's disease. Neurobiology of Aging, 25(1), 5-18.

http://www.eurekalert.org/pub_releases/2003-12/uoc--mbc122303.php

A nicotine by-product implicated in Alzheimer’s

A previously unrecognized chemical process has been discovered, by which a chemical called nornicotine, naturally present in tobacco and produced as a metabolite of nicotine, permanently and irreversibly modifies proteins in the body. These modified proteins interact with other chemicals in the body to form a variety of compounds known as advanced glycation endproducts. Advanced glycation endproducts have previously been implicated in numerous diseases including diabetes, cancer, atherosclerosis, and Alzheimer’s disease.

Dickerson, T.J. & Janda, K.D. 2002. A previously undescribed chemical link between smoking and metabolic disease. Proc. Natl. Acad. Sci. USA, 99 (23), 15084-15088.

http://www.eurekalert.org/pub_releases/2002-10/sri-aka102402.php