Tag Archives: Phospholipase D3

111 years of study of the Alzheimer plaque still got it wrong (until now)

The senile plaque of Alzheimer’s disease has been known for 111 years  which is when Alzheimer’s first patient died and he studied her brain. For the past 60 or so years, we’ve studied it using every technique at our disposal.  We know its chemistry fairly  well, and understand many of the mutations that cause the familial forms of Alzheimer’s disease.

However, we’ve still been interpreting its structure incorrectly until this month.  In addition to the amorphous gunk of the plaque, electron microscopy has described swollen ‘dystrophic neurites’ in and surrounding the plaque.  The semantics of neurites implies a small nerve process which led us all down the garden path to assume that they are dendrites (which are usually smaller than axons).  Wrong, wrong, wrong, they are axons as a recent paper proves conclusively [ Nature vol. 612 pp. 328 – 337 ’22 ].

It took a lot of technology to reach this point.  First was development of the 5XFAD mouse which gets plaques galore, because it contains 5 mutations spread over two proteins, the amyloid precursor (APP) protein from whence the aBeta peptide of the senile plaque and PSEN1 a protein which helps to process APP into aBeta.  Second was the ability to observe dendrites and axons in the living (mouse) brain for long periods using specialized microscopic techniques and a variety of dyes and fluorescent proteins.  They allow us to watch action potentials pass along axons without sticking an electrode into them (by measuring rapid changes in local calcium concentration).

Each senile plaque contained hundreds of axons with focal swellings (the dystrophic neurites).  Most were present for months, but some disappeared without axon loss.  When an action potential got to a focal swelling (also known as a spheroid) it slowed down (the swelling acts as a sink for the current  due to its ability to store ions  (higher capacitance).  Random slowing of nerve conduction is murder for information processing.  It’s old technology but just think of what happens when you play  of  a 33 rpm record at 78 rpms.  It’ s also why the random demyelination (which changes action potential velocity)  of nerve fibers in MS raises hob with information transmission hence neurologic function.

Why did electron microscopy miss this?  Because it is just a two dimensional (very thin) slice of dead brain.

The paper has a lot more about what’s in the swelling — large endolysosomal vesicles, and a possible way to treat Alzheimer’s — genetic ablation of phospholipase D3 (PLD3) was able to reduce the average size of the dystrophic neurities and improve axon conduction.

It’s actually a hopeful paper, because we’ve been assuming that the dystrophic neurites were either dead, severed  or nonfunctional, and here they are intact and conducting nerve impulses.

Like all great scientific papers, it raises more questions than it answers.  Is the swelling due to extracellular aBeta?  Is the swelling an attempt to internalize aBeta and destroy it?  Is there a way to inhibit PLD3 ?   Genetic ablation of a gene in a living human is at or beyond our current technology.