Mad-cow disease, Alzheimer’s, and nanosecond-memory-accesses?

Dr. Harvey mentioned some very cool things.

Infectious agents, basically, are transferring information. How do you copy information? Well, use a two-stranded molecule, split it up, and replicate (makes me think of bit inversion with bases!) That explains why Dr. Widrow would assume that “innate” memory – transferred along generations – might be R/DNA based (mild pun intended). But nucleic acids aren’t the only infectious agents around. Proteins (aha, neurons have a lot!) can misfold and cause a lot of problems. Can they be linked to memories, and by a long shot, to Alzheimer’s?

Prion ]: an infectious agent composed of protein in a misfolded form.[2] This is the central idea of the Prion Hypothesis, which remains debated.[3] This would be in contrast to all other known infectious agents, like virusesbacteriafungi or parasites—which must contain nucleic acids (either DNARNA, or both).

The Return of the Prion Hypothesis.

[ Jim Schnabel, Dana article, 2012 ]

Because the novel properties of the scrapie agent distinguish it from viruses, plasmids, and viroids, a new term “prion” is proposed to denote a small proteinaceous infectious particle which is resistant to inactivation by most procedures that modify nucleic acids [i.e., DNA or RNA]. Knowledge of the scrapie agent structure may have significance for understanding the causes of several degenerative diseases.

Stanley Prusiner, 1982 ]

Alzheimer’s features a slow accumulation of A-beta plaques throughout the brain | [ Beyreuther ] A-beta protein is a fragment—the remainder after a cutting by enzymes—of a much larger neuronal membrane protein…APP…coded by a gene on chromosome 21.

[ APP: an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. ]

APP-overexpressing mouse models…developed plaques, but did not develop the…neurofibrillary tangles, which are made of tau protein and appear inside affected neurons…Most families with APP mutations were found not to overexpress A-beta…but to overexpress a comparatively rare, aggregation-prone version, known as A-beta-42.

Were A-beta plaques the wrong target? Were the tau tangles the true culprits? Or were both these amyloids “red herrings”?

A-beta…, besides forming long, plaque-making fibril aggregates, can cluster into tiny, soluble “oligomers”

[ William Klein: memory-linked synapse structure and signal transduction ] [ talk ]

Researchers also found evidence that other amyloid-forming proteins, such as tau, Parkinson’s disease-related alpha synuclein protein, Huntington’s disease-related huntingtin protein, and even the PrP protein implicated in prion diseases, are toxic to neurons principally as oligomers, not as large amyloid fibrils.

These oligomers seem to share a common…“conformation” that makes them toxic somehow. A number of labs including Charles Glabe’s…have made conformation-specific antibodies that can recognize toxic oligomers of many of these proteins despite their very different amino-acid sequences.

…circumstantial evidence that the buildup of A-beta aggregation over decades eventually triggers tau aggregation—which represents the last, lethal stage of disease.

 

[ APP PDB ]

Linking APP and memory

Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory ]

From the abstract:

Here we review evidence addressing these fundamental questions, paying particular attention to the contributions that APP fragments play in synaptic transmission and neural plasticity, as these may be key to understanding their effects on learning and memory. It is clear from this literature that APP fragments, including Aβ, can exert a powerful regulation of key neural functions including cell excitability, synaptic transmission and long-term potentiation, both acutely and over the long-term. Furthermore, there is a small but growing literature confirming that these fragments correspondingly regulate behavioral learning and memory. These data indicate that a full account of cognitive dysfunction in AD will need to incorporate the actions of the full complement of APP fragments.

More people

[ Louise T. Chow ]

Sci-fi section?

Anyway, if you were to design a memory architecture using proteins, how would you do it? Is that how biology does it? Are neurons collections of transistors and APP-based memory cells? Would such thoughts lead to a von-Neumann-like-bias in understanding, perhaps an alternative computation paradigm? Now where’s sic-fi when you need it…

 

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