Research in 2007 plowed new ground in understanding and treating neurodegenerative diseases, including Alzheimer’s. A growing body of evidence is also leading to new insights into how the brain uses memories of the past to plan for the future.
No treatment has yet been proved to modify the course of Alzheimer’s disease, but researchers are drawing close on a number of fronts that, in combination, may advance treatment and maybe even prevention of Alzheimer’s disease. A protein called beta-amyloid is one focus, but research continues on other targets as well.
Beta-amyloid and Alzheimer’s
Several of the research advances concern beta-amyloid protein plaques and fibrils, which build up in the brains of patients with Alzheimer’s disease. Plaques form in spaces between brain cells, and fibrils (tangles) develop within brain cells, but research suggests that neurons are damaged and brain functions are impaired before such structures appear.
Results of diverse studies using synthetic beta-amyloid peptides, cell culture models, transgenic mice (genetically engineered to contain human DNA), and the human brain all point in one direction: progressive accumulation of beta-amyloid is toxic to cells long before visible plaques and fibrils form. The subunits, or building blocks, of beta-amyloid protein were the subject of much research in 2007.
A team led by Lennart Mucke at the University of California, San Francisco, studied transgenic mice that have large amounts of beta-amyloid subunits in their brains; the animals exhibit many of the symptoms of Alzheimer’s, including cognitive deficits.1
The researchers found high levels of nonconvulsive seizure activity in the hippocampus and cortex, structures known to be important to memory. In those regions, beta-amyloid subunits cause an increased rate of firing in certain excitatory neuronal circuits. In response, inhibitory circuits remodel themselves. The effect is a reduction in the firing rate of the excitatory circuits.
The team concluded that the cognitive deficits associated with Alzheimer’s disease may result from the combination of excessive neuronal firing, caused by beta-amyloid subunits, followed by compensatory remodeling of inhibitory circuits. The remodeling may impair the function of the excitatory circuits.
Mucke suggests that treatments that block beta-amyloid-induced over-excitement of neurons might prevent the activation of inhibitory pathways, their subsequent remodeling, and the cognitive impairments that ensue.
Elsewhere, a Northwestern University team led by William Klein investigated how beta-amyloid-driven subunits called ADDLs affect synapse composition, structure, and abundance.2 These molecules build up in the brain and the cerebrospinal fluid. They attach to synapses, where they interfere with plasticity, the ability of the synapse to change. Eventually, the synapse degenerates, bringing on the memory loss of early Alzheimer’s disease.
Klein and his team investigated dendritic spines, which are outgrowths on the smaller, branching extensions of neurons. In most neurons, dendrites carry impulses toward the nerve cell body.
Using neurons cultured from the hippocampus, Klein and his colleagues found that ADDLs bind to dendritic spines in specific kinds of neurons and cause an increase in the number of certain memory-related receptors. Continued exposure leads to abnormally long, thin dendritic spines and, eventually, to a reduction in the number of spines. As a result, synapses deteriorate. The anti-Alzheimer’s drug Namenda blocks both effects, the researchers found.
In a related study, a team led by Bernardo Sabatini at Harvard demonstrated that two- and three-molecule subunits (but not single-molecule subunits) from beta-amyloid-derived proteins brought on progressive loss of synapses in hippocampal cells.3 The density of spines on dendrites and the number of active synapses in pyramidal neurons declined after exposure to the small, soluble molecules.
Beta-amyloid-specific antibodies reversed the loss of spines, as did a substance that prevented the buildup of the small molecules into larger units. Sabatini concluded that small, soluble subunits of beta-amyloid trigger the loss of synapses.
The exact molecular structure of these soluble, diffusible subunits that merge into visible plaques and fibrils is still being probed. Nevertheless, therapies aimed at preventing the production of the subunits are being developed and tested. The goal of such treatments is to slow or even halt the deterioration of neuronal circuits before Alzheimer’s symptoms appear.4
Beta-amyloid is made from amyloid precursor protein (APP) in several parts of the cell. One important step in beta-amyloid manufacturing occurs during the re-entry and recycling of APP as it moves from the cell surface through a specific pathway inside the cell. A large international team of researchers led by Peter St. George-Hyslop of the University of Toronto reasoned that inherited differences in that pathway might affect both the processing of APP and the risk of developing Alzheimer’s.
They reported in Nature Genetics that inherited differences in a gene called SORL1 are associated with late-onset Alzheimer’s disease.5 The variants occur in at least two different clusters of noncoding DNA within the SORL1 gene. These clusters may regulate how SORL1 is expressed in brain tissues.
The team found that SORL1 directs APP into recycling pathways. When there is a shortage of SORL1, APP is sorted into compartments where beta-amyloid proteins form. The researchers concluded that inherited or acquired changes in SORL1 expression or function are one cause of Alzheimer’s disease.
Other Targets for Treatment
Beta-amyloid proteins are not the only targets for potential Alzheimer’s treatment. Another is a protein called tau.
Tau is abundant in normal neurons. It interacts with the protein tubulin to promote and stabilize microtubules, the hollow, cylinder-shaped structures in a cell that support it and move materials through it.
However, certain abnormal forms of tau can trigger the assembly of the tangles and filaments found in the neurons of Alzheimer’s patients. Researchers are attempting to learn whether treatments aimed at tau can block beta-amyloid-induced cognitive impairments.
A team led by Eric Roberson at the Gladstone Institute of Neurological Disease in San Francisco used transgenic mice to probe this question. The mice were engineered to express high levels of amyloid precursor protein. They were tested in a water maze for learning and memory. Roberson found that reducing tau levels in tissues preserved the animals’ ability to learn the maze, even though their beta-amyloid levels were high.
In addition, Roberson found that tau reduction protected both transgenic and nontransgenic mice against something called excitotoxicity, which occurs when a type of amino acid in the brain becomes toxic to neurons. The study, published in Science, concluded that reducing tau can block both beta-amyloid and excitotoxic dysfunction in neurons.6 Thus, tau reduction may represent an effective strategy for treating Alzheimer’s disease and related conditions.
Another potential therapy is a peptide called NAP that has been shown to protect against beta-amyloid-induced neuron death. NAP appears to block the buildup of beta-amyloid into plaques and fibrils. It also binds to tubulin, thereby preventing the microtubule disruption associated with Alzheimer’s.
Paul Aisen and his research team at Georgetown University studied transgenic mice that show both hallmarks of Alzheimer’s: accumulation of beta-amyloid and the modified forms of tau associated with microtubule dysfunction. The team gave the mice daily doses of NAP for three months, beginning at age nine months—before disease symptoms appeared.
They reported in the Journal of Molecular Neuroscience that the treatment significantly lowered beta-amyloid levels in the animals’ brains.7 NAP also reduced levels of abnormal tau. The researchers conclude that NAP might offer promise as a treatment for Alzheimer’s.
Meanwhile, researchers at the Massachusetts Institute of Technology studied mice in which they could control the loss of neurons in certain places and for short periods. Some of the mice were placed in an “enriched environment”—their cages contained running wheels, toys, tunnels, and climbing devices. In this enriched environment, the mice regained their learning behavior and reestablished access to long-term memories, even after brain atrophy and neuronal loss had occurred.
The team studied the genetic material present in the brain tissue of the mice. The scientists were especially interested in the histone tails of chromatin, the complex of DNA and proteins that makes up chromosomes. Chromatin strands contain histones, a type of protein around which DNA coils. Histones are what primarily make up the tails, or ends, of chromatin strands.
The researchers found that chemical changes in these histone tails occurred when the environment was enriched. When those same changes were induced by a drug that inhibits the activity of a related enzyme called HDAC, dendrites sprouted, the number of synapses increased, and learning behavior and access to long-term memory improved. The researchers concluded in their May 10 Nature article that drugs that inhibit the enzyme might help in treatment of Alzheimer’s and other forms of dementia.8
Other researchers are probing how HDAC enzyme inhibitors work. Do they alter the expression of many genes and affect memory processes in a general way? Or is their action targeted? One study found two specific effects. One relates to a protein called CREB, which is formed inside the neuron and is known to be important to memory formation. Inhibitors also affect the expression of several individual genes during memory consolidation.9
A team led by David Holtzman at Washington University in St. Louis reported in the Archives of Neurology in March 2007 that ratios of certain types of beta-amyloid and tau can help identify whether someone with normal cognition has amyloid deposits in the brain, increasing the chances that dementia will develop.
The researchers analyzed the cerebrospinal fluid and blood of 139 volunteers, ages 60 to 91, who had been diagnosed as cognitively normal or having very mild or mild dementia.10 The team found that individuals with very mild or mild Alzheimer’s have less of a certain type of beta-amyloid and more tau in their cerebrospinal fluid than healthy controls. Levels of this beta-amyloid type predicted whether amyloid was present in the brains of people with and without dementia.
Remembering and Imagining
Also in 2007, a growing number of researchers explored the relationship between remembering the past and imagining the future. People who have suffered damage to the hippocampus have difficulty remembering past events and imagining future scenarios. People with schizophrenia also recall fewer specific past events and imagine fewer specific future events than do normal subjects, reported Arnaud D’Argembeau of the University of Liège in Belgium. The research is reported in the Journal of Abnormal Psychology.11
Similar findings emerged in a Harvard study reported in Psychological Science. A team of researchers studied episodic memory in healthy older adults and college students. Episodic memory is important because it allows the recall of personal incidents that uniquely define an individual’s life. It lets people project themselves both backward and forward in subjective time.
When the team asked the volunteers to generate past and future events, the older adults came up with fewer episode-specific details relating to past events than younger adults did. The same effect occurred for future events: imagined happenings contained less episodic information.12 One result of the loss of episodic memory is that older adults sometimes have trouble integrating information and forming relations between items.
Neuroimaging studies show evidence of shared brain regions for remembering the past and imagining the future. In one study, 21 volunteers raging in age from 18 to 32 underwent magnetic resonance imaging while remembering past events and imagining future events in response to event cues.13 The scans revealed a striking overlap in the activity associated with past and future events: the processes of remembering the past and imagining the future are associated with a core brain system that includes the prefrontal and medial temporal lobe regions, as well as posterior regions (including the precuneus and the retrosplenial cortex) that are consistently observed as components of the brain’s memory retrieval network.
Findings such as these have led to the concept of the “prospective brain,” the idea that the brain uses stored information to imagine, simulate, and predict possible future events. The concept offers a new way of thinking about and studying memory, according to Harvard psychologists Daniel Schacter, Donna Rose Addis, and Randy Buckner.14 It suggests that both remembering and imagining use shared networks to retrieve stored information.
Imagining, however, requires the recombination of details in new ways, for which additional brain regions must be recruited. This overlap may explain why recall fails as a perfect recording of the past and functions instead as a constructive process. The ability to reorganize and reshape information stored in memory may be crucial to planning for the future, Schacter, Addis, and Buckner say.
1. Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, Yoo J, Ho KO, Yu G-Q, Kreitzer A, Finkbeiner S, Noebels JL, and Mucke L. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron 2007 55(5):697–711.
2. Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, and Klein WL. Beta-amyloid oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. Journal of Neuroscience 2007 27(4):796–807.
3. Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, and Sabatini BL. Natural oligomers of the Alzheimer amyloid-β protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. Journal of Neuroscience 2007 27(11):2866–2875.
4. Walsh DM and. Selkoe DJ. Beta-amyloid oligomers: A decade of discovery. Journal of Neurochemistry 2007 101(5):1172–1184.
5. Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, Katayama T, Baldwin CT, Cheng R, Hasegawa H, Chen F, Shibata N, Lunetta KL, Pardossi-Piquard R, Bohm C, Wakutani Y, Cupples LA, Cuenco KT, Green RC, Pinessi L, Rainero I, Sorbi S, Bruni A, Duara R, Friedland RP, Inzelberg R, Hampe W, Bujo H, Song Y-Q, Andersen OM, Willnow TE, Graff-Radford N, Petersen RC, Dickson D, Der SD, Fraser PE, Schmitt-Ulms G, Younkin S, Mayeux R, Farrer LA, and St. George-Hyslop P. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nature Genetics 2007 39(2):168–177.
6. Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu G-Q, and Mucke L. Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer's disease mouse model. Science 2007 316(5825):750–754.
7. Matsuoka Y, Gray AJ, Hirata-Fukae C, Minami SS, Waterhouse EG, Mattson MP, LaFerla FM, Gozes I, and Aisen PS. Intranasal NAP administration reduces accumulation of amyloid peptide and tau hyperphosphorylation in a transgenic mouse model of Alzheimer’s disease at early pathological stage. Journal of Molecular Neuroscience 2007 31(2):165–170.
8. Fischer A, Sananbenesi F, Wang X, Dobbin M, and Tsai L-H. Recovery of learning and memory is associated with chromatin remodelling. Nature 2007 447:178–182.
9. Vecsey CG, Hawk JD, Lattal KM, Stein JM, Fabian SA, Attner MA, Cabrera SM, McDonough CB, Brindle PK, Abel T, and Wood MA. Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB: CBP-dependent transcriptional activation. Journal of Neuroscience 2007 27(23): 6128–6140.
10. Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, and Holtzman DM. Cerebrospinal fluid tau/β-amyloid42 ratio as a prediction of cognitive decline in nondemented older adults. Archives of Neurology 2007 64(3):343–349.
11. D’Argembeau A, Raffard S, and Van der Linden M. Remembering the past and imagining the future in schizophrenia. Journal of Abnormal Psychology (in press for December 2007 or January 2008).
12. Addis, DR, Wong AT, and Schacter DL. Age-related changes in the episodic simulation of future events. Psychological Science (in press for January 2008). Prepublication copy available at http://www.wjh.harvard.edu/~dsweb/pdfs/inpress_DRA_ATW_DLS.pdf
13. Szpunar KK, Watson JM, and McDermott KB. Neural substrates of envisioning the future. Proceedings of the National Academy of Sciences USA 2007 104(2):642–647.
14. Schacter DL, Addis DR, and Buckner RL. Remembering the past to imagine the future: The prospective brain. Nature Reviews Neuroscience 2007 8(9):657–661.
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