Is it conceivable that that dementia of Alzheimer’s disease could be reversed (and quickly)?

I saw people get out wheelchairs in 1970 in just a few weeks after starting L-DOPA (which had just been released in the USA) for their Parkinson’s disease.  Could anything remotely similar happen in Alzheimer’s disease?  I think it’s possible if the problems with thinking and forming new memories are due to the senile cluttering up the brain (a very big if).  First, more than just a little bit of neuroanatomic and neurophysiologic background.

As recently as 1900,  it was far from clear that the brain was actually made of cells, unlike every other tissue in the body.  Why?  Because the smallest wavelength of visible light is 4000 Angstroms, and nerve cells in the brain  are mushed together far more closely than that.  With the invention of the electron microscope we could see nerve processes, including dendrites and dendritic spines in glorious detail. Dendritic spines are the major place in the brain where neurons communicate with each other (the synapse between axon and dendrite).  The latest estimate is that we have trillions of dendritic spines on our billions of neurons.  People have been able to see dendritic spines even at the resolution of the light microscope for the past century using silver staining techniques. But to see them, you had to kill the animal, fix the brain and make microscope slide.

Subsequently it became possible to watch dendritic spines form between neurons in tissue culture using various fancy types of microscopy (confocal laser microscopy etc. etc. ).

For about the past 10 years we’ve been able to observe dendritic spines for months in the living (rodent) brain.  In 1970, if you told me that, I’d have said you were smoking something.  The surprising finding is that dendritic spines are a work in progress, being newly formed and removed all the time.  The early literature (e.g. 10 years ago) is contentious about how long a given spine lasts, but most agree that spine plasticity is present every time it’s looked for.  Here are a few references [ Neuron vol. 69 pp. 1039 – 1041 ’11, ibid vol. 49 pp. 780 – 783, 877 – 887 ’06 ].

What does this have to do with Alzheimer’s? It seems likely that learning new things involves not just the strengthening of synapses (making them more likely to transmit information), a concept going back 50 or so years to Hebb, but the formation of new ones. Here are a bunch of pictures of such plaques

There has been a huge amount of discussion about how (and even if) the senile plaque causes the cognitive problems of Alzheimer’s.  Most of the dementia of Alzheimer’s has been attributed to the loss of neurons.  The plaques are thought (by some) to cause the neuronal loss.  Perhaps they do, but what if the plaques are causing cognitive problems by simply getting in the way of new synapse formation (e.g. sand in the gears of the brain).  Then getting rid of the plaques should help cognition.

Alzheimer therapy is ineffectual at best, but it isn’t from lack of trying to get rid of plaques.  Antibodies against the major protein component of the plaque (Abeta peptide) unfortunately caused inflammation of the brain in some patients and had to be abandoned.  Bapineuzumab  has shown minimal results so far. In mice Bexarotene (Targretin)  looks promising, but here   the mechanism involves a protein (apolipoprotein E) which is quite different in mouse than man.

This brings us to an older post —  Again, the work is in the mouse, but the preparation causes an enzyme in the liver to chew up Abeta peptide, with a marked decrease in plaque numbers and size and improvement in mental functioning in the mice (assuming you can actually measure such things).  The nice thing about this work, is that the preparation doesn’t even have to get into the brain.

We’re not going to raise neurons from the dead.  New neurons form in the human brain quite rarely (despite claims to the contrary – I frankly don’t believe Gage’s work), but hopefully we might be able to make those left function better.  The preparation is from Ayurvedic medicine, and people have been taking the stuff for millenia without dying on the spot.  It’s time to find out what the active principle actually is in the preparation, and get to work.

Addendum 11 Apr ’12:  Cell vol. 148 p. 1204 ’12 — tending to cast a favorable light on the hypothesis above — “Although Alzheimer’s disease clearly causes loss of neurons in specific brain regions  . . . .  much of the overall loss of brain volume appears o be due to the shrinkage and loss of neuronal processes.”  So if there hasn’t been that much death, the possibility of rejuvenating the survivors looms larger.

Against my idea is that fact that a cognitively intact individual can have tons of  senile plaques at autopsy.

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  • dicky_dooo  On April 11, 2012 at 12:54 pm

    Regarding Bexarotene, you say “so far in man, the results have been minimal”.
    What do you base this statement on?

  • luysii  On April 11, 2012 at 1:55 pm

    Very good ! I meant bapineuzumab. Here’s the link. I’ve changed things a bit. Thanks

  • Anthony  On April 12, 2012 at 3:14 pm

    There’s a hypothesis that arterial plaques are a symptom of an underlying problem, and that treatments which reduce them might lower the risk of heart attack, but not solve the underlying problem. Is it possible that the plaques in Alzheimer’s are similar – they develop in response to something else going on?

  • Paul  On April 17, 2012 at 3:49 pm

    Despite the link between amyloid and AD, plaque load doesn’t correlate with cognitive decline [1]. So it seems unlikely that removing plaque will reverse AD, as confired in the antibody trials. The Betaroxone study oddly enough showed that betaroxone’s effect were much smaller in older mice than young mice; that angle is still early days, and I understand that clinical trials are currently ongoing.

    [1] P. V. Arriagada, J. H. Growdon, E. T. Hedley-Whyte, and B. T. Hyman, “Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease,” Neurology, vol. 42, no. 3, pp. 631–639, 1992

    • luysii  On April 17, 2012 at 4:00 pm

      Agree — I actually put in an addendum at the bottom the following day to this effect. However, evidence about pathogenesis is rarely clearcut (just look at the many interpretations of just what form the Abeta culprit actually takes — monomer, multimer, insoluble mess etc. etc.). Of interest is the following: [ NeuroBiol. Aging vol. 64 pp. 632 – 644 ’09 ] A recent genome wide association study (GWAS) found reelin variant genes which were associated with normal cognitive function in the elderly with substantial “Alzheimer-like” pathology. I haven’t read the actual paper, so I don’t know how pathology was actually determined.

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