Scientists Map Brain's Primary Memory Network / Alzheimer's Breakthrough

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Scientists Map Brain's Primary Memory Network / Alzheimer's Breakthrough

Thursday, December 09, 1999

For the first time, a team of Wake Forest University investigators has

mapped the functional organization of the hippocampus, the brain's primary

memory network, a step that other scientists are calling " a major

breakthrough. " The researchers - Sam A, Deadwyler, Ph.D., E.

Hampson, Ph.D. and D. Simeral - report in today's (Dec. 9) Nature that

they have mapped the way that a part of the brain, the dorsal hippocampus,

encodes information when rats perform a short-term memory task.

The researchers, members of the Department of Physiology and

Pharmacology, mapped the actions with an array of 10-16 microelectrodes. The

electrodes are small enough to record the electrical impulses of individual

brain neurons during the animals' performance. Recordings from the

electrodes demonstrate that different portions or segments of the

hippocampus are active at different times during the task depending on the

type of memory function required.

In the " News and Views " section of the same issue of Nature,

Eichenbaum, Ph.D., of the Laboratory of Cognitive Neurobiology at Boston

University termed the breakthrough in understanding memory processes highly

significant, adding that the study revealed " a functional organization for

the hippocampus, one of the highest cortical processing areas in the brain. "

The rats are tested in an experimental chamber with two bars or levers

positioned on a single wall as left or right. At the start, only one lever

is presented. It is pressed by the animal, then retracted, followed by a

delay period in which the rat must engage in other unrelated activity. The

delay period can be as short as one second or as long as forty seconds --

the rat never knows. At the end of the delay, both levers appear, and the

animal is supposed to press he lever it did not press at the outset of the

trial. If it does, it is rewarded. If the wrong lever is pressed the chamber

goes dark for five seconds and a new trial begins.

" The uniqueness of this situation is that the animal's task is to

remember one piece of information in one phase of the task, that is, which

lever it pressed before the delay, and then retain and use that information

to make a decision about which lever to press when both levers are available

after the delay is over, " said Deadwyler, professor and vice chair of the

department.

The task is easy if the delay is short -- the animal will get the

answer correct most of the time. However, as the delay becomes longer it is

more likely that animals will not remember which lever it pressed at the

start and chose the wrong lever at the end of the delay. Deadwyler noted

that is similar to the rapid decrease in retention of a new telephone number

after it is dialed.

Animals played the game between 100 and 150 times each day and

generated very stable performance profiles.

While the animals were performing, the researchers were recording which

neurons in the hippocampus were active and found different patterns,

depending on which lever the animal was supposed to choose at end of the

trial. " There's a distinct separation up and down the hippocampus with

respect to which groups of cells fire during the different phases of the

memory task, " Deadwyler said.

" The findings extend this knowledge of hippocampal encoding to an

anatomic framework of overlapping 'memory networks' in which location within

hippocampus determines which cells are activated under which short-term

memory demands, " the team reported.

In his commentary, Eichenbaum points out that the anatomic framework

described by Deadwyler and colleagues follows known functional anatomy

present in other brain areas that are not specialized to encode memories,

indicating that " the coding properties of hippocampal neurons 'respect' the

anatomical circuitry in which they reside. "

Deadwyler said the work parallels ongoing studies in people in which

scientists are trying to determine how subjects encode different types of

information and how retrieval of that information occurs in different brain

regions. " There might be a similar anatomic encoding scheme in the human

hippocampus for categorizing and partitioning information used in short term

memory as we have seen in the rat. "

Hampson is associate professor and Simeral is a third-year graduate

student.

* * *

Alzheimer's Breakthrough

[Protein found that turns brain enzyme into possible trigger for

Alzheimer's tangles.]

Breaking an impasse in Alzheimer's research, Harvard Medical School

scientists have identified in the brains of patients a protein, called p25,

that can initiate the subtle molecular changes known to lead to

neurofibrillary tangles, one of the disease's pathological hallmarks.

Reported as a full article in the December 9 Nature, the study builds a

systematic case against p25. This small protein, the researchers claim, can

divert an enzyme called cdk5 from its day-to-day work in the brain and turn

it into a menace that ultimately destroys neurons.

" We believe that the production and accumulation of p25 in the

Alzheimer's brain very likely plays a role in the pathogenesis of the

disease, " says senior author Li-Huei Tsai, associate professor of pathology

at Harvard Medical School.

The study supports one of the two major attempts at explaining this

complex condition. The hypothesis holds that a long-sought but still

mysterious enzyme attaches many phosphate groups to a normal protein called

tau, which stabilizes the neuron's inner skeleton, helping the cell maintain

its extended connections with neighboring and distant cells. This

hyperphosphorylation is known to set in motion a deadly neurodegenerative

cascade that shows up in postmortem exams as tangles of intertwined tau

filaments cluttering the cells' inside.

In recent years, this hypothesis languished as another line of thought,

which centers on extracellular beta-amyloid plaques, has made rapid progress

identifying protein components, enzymes, and the biochemical process of how

plaques form.

It was not for lack of trying. Many tau laboratories have for years

sought the enzyme, or kinase, that hyperphosphorylates tau. Indeed, many

kinases do so when nudged in biochemical tests, but none appeared overly

active in early Alzheimer's disease until now. Tsai's paper " is a major

advance in this search, " writes tangle expert Eckart Mandelkow of the

Max-Planck-Unit for Structural Molecular Biology in Hamburg, Germany, in an

accompanying News and Views article.

Yet while her study gives a lift to the tangle view of Alzheimer's,

Tsai does not promote one theory at the expense of the other. Rather, she

considers this study the first chapter in a fast-evolving story that may

soon unite both ideas.

That is because a new trend is afoot as developmental neurobiologists

realize that cdk5, their " favorite " molecule - whose precise role in brain

formation they have been trying to parse-might also function in

neurodegeneration. Take Tsai, for example. In previous work, she discovered

that when controlled by its protein partner p35, the kinase cdk5 helps newly

generated neurons deep inside the embryonic brain migrate outwards past

their older cousins, thus enabling the cerebral cortex's characteristically

layered pattern to form properly.

Trying to confirm other scientists' data that cdk5 can also work with

p25 - a fragment of p35 - Tsai tried hard to find p25 but failed. That is,

until first author Gentry decided to look in diseased human brain.

There it was, at last: p25 proved to be accumulated 20- to 40-fold in

cortical neurons of people with Alzheimer's. Its amount correlated with the

progression of the disease in that later stages harbored more p25.

" That was very exciting. It really opened our eyes and initiated this

whole investigation, " recalls Tsai.

From then on, things fell into place. P25, it turned out, misses the

piece of its parent p35 that anchors p35 to the neuron's cell membrane,

where it belongs. What's more, p25 is stable, whereas p35's half-life is but

20 minutes because it gets degraded in the cell's waste disposal organelle.

Taken together, this means that the careful controls on space and time that

p35 exerts over cdk5 all fall away with p25. Once made, it can hang around

the cytoplasm and send cdk5 on a " phosphorylation binge. "

Tsai says she was struck by how readily p25/cdk5 managed to undo the

neurons. First, several different experiments indicated a disintegration of

the cultured neurons' microtubules - the main struts of the cell's inner

skeleton and its major transport rails. Second, the neurons then withdrew

their processes, and shriveled to being mere rounded cell bodies.

The second major implication of this study results directly from this

apparent degeneration: within three days, 90 percent of the cultured neurons

expressing p25/cdk5 were dead. What's more, they died by programmed cell

death, or apoptosis, the authors show. Scientists at Harvard and elsewhere

are pursuing intensely the question of how neurodegeneration eventually

seals a cell's fate, and this study offers a new handle on the underlying

molecular pathways.

Whether p25/cdk5 actually wreaks the kind of havoc in people's brains

that it causes in cultured neurons remains to be proven. But now that Tsai

and her collaborators have established this phenomenon, others can test its

significance, for example, by trying to slow or reverse neurodegeneration in

Alzheimer's animal models with inhibitors of cdk5 or p25.

The work also raises the question whether cdk5 plays a general role in

neurodegeneration. Other " tauopathies " exist, including progressive

supranuclear palsy and a type of dementia called FTDP-17. Moreover, cdk5 is

known to accumulate in motor neurons with Lou Gehrig's disease.

For her part, Tsai is intrigued by the fact that the suspect she nabbed

is not an entirely novel molecule found only in a disease. Instead, it is a

workhorse of an enzyme that - properly reined in - functions in

indispensable ways in the developing and the adult human. But unleash p25,

and cdk5 turns destructive. " The most pressing questions right now are,

" What is the mechanism converting p35 into p25 and What conditions induce

this conversion? " she adds. Stay tuned.

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