A DISRUPTIVE APPROACH TO NEURODEGENERATION

What is the idea and why is it so novel?

One of the most glaring, yet under-explored, aspects of AD is that not all neuronal groups are equally vulnerable. Neurodegeneration does not automatically follow after brain injury nor stroke, and this should surely prompt the question: why not?

Moreover, a survey of the literature (Bondareff et al, 1987, Braak & Del Tredici, 2012) reveals a large number of reports identifying the primarily vulnerable cells in AD, i.e., those that degenerate first, as the interconnecting subcortical cell groups extending from the basal forebrain to Raphe nuclei, ventral tegmental area, substantia nigra, locus coeruleus and motor neurons.

If we could identify the common feature of these cell groups that distinguished them from all the other neurons in the rest of the brain, then surely that would provide a clue as to the basic mechanism itself that drives the continuing feedforward cycle of cell loss.

Accordingly, if any of the basal plate derived cell groups are damaged for whatever reason, such as a blow to the head, a transient ischaemic attack, or a decline in scavenging mechanisms, the outcome will be different from that of an equivalent insult to their alar plate derived counterparts.

Unlike in the rest of the brain, this damage will trigger in retaliation the homeostatic mechanism of compensatory cell growth selectively retained by these particular cells into adulthood. However, the problem is that now the brain is fully mature and the amount of calcium influx that would normally have enabled cell growth during development, will be excitotoxic in the context of the older brain: hence more cells will die and the cycle of cell loss will be perpetuated and amplified.

The erstwhile feedback system has now become one of feedforward toxicity that we recognise as neurodegeneration.

If the cells prone to AD degeneration are characterised by an inappropriately activated signalling system for cell growth, it might be expected that they operate by means of a common transmitter system: but this is not the case. A range of diverse amines characterise and operate in the respective nuclei: dopamine in the VTA substantia nigra groups, 5-HT in the Raphe nuclei, norepinephrine in the locus coeruleus and acetylcholine (ACh) in the basal forebrain (Woolf, 1996) and Fig 1. However, irrespective of diverse transmitter systems, all of these cells do express a common molecule: the very familiar enzyme acetylcholinesterase (AChE), Fig 2.

What is the salient part of the AChE molecule driving neurodegeneration?

The G4 form of AChE is dependent on disulphide bonds which include a 14mer peptide at the C terminus, with homology to Aβ (Greenfield & Vaux, 2002). The potentially bioactive active part of the AChE molecule has thus been identified as this peptide, ‘T14’: AEFHRWSSYWVHWK (Fig 3).

How does T14 work?

However, the most cogent reason for suspecting that this receptor might be the target for T14, is that it coexpresses almost in lockstep with the appearance of AChE in the developing brain (Broide et al, 1996), even in areas where there is no cholinergic transmission. Ex vivo studies have exploited the symmetry of the brain in coronal section, to separate down the midline the two hemi-sections of living brain slice, incubating one side with T30: the result was an enhancement of both Aβ and tau from the treated sections, compared to the perfectly matched, but untreated control side (Brai et al, 2017), Fig 4.
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The T14 trophic-toxic pathway has been investigated using selective blockers of intracellular events (Day & Greenfield, 2004) and can then be traced as follows: T14 will bind (greenfield at al, 2004) to an allosteric site on the alpha 7 receptor to enhance calcium influx (Bon & Greenfield, 2003), causing depolarization and activation of voltage sensitive calcium channels (Dickinson et al, 2007). The net increase in intracellular calcium activates the cascades shown in the diagram (Fig 5).

How can T14 be blocked?

NBP14 has proved in both in vitro (Garcia-Ratés et al, 2016) and ex vivo studies (Badin et al, 2016; Brai et al, 2018) to be non-toxic when applied alone, but protective against a range of linear peptides: Aβ, T14, and T30, the more stable peptide containing the active component T14 (Bond et al, 2009). The drug appears to have no effects other than blocking the action of its linear counterpart on: calcium influx, cell viability, and AChE release in PC12 cells, where it also blocks the toxic effects of amyloid (Figure 6).

In addition, within the CNS, NBP14 blocks the action of T14 on large scale neuronal activity, as monitored with optical imaging in living brain slices (Badin et al, 2016). In a subsequent ex vivo preparation, it was shown that NBP14 competes with T14 for its binding site (Brai et al, 2018).

Why does this particular approach hold out more promise for understanding and treating AD?

On the other hand, it is surely only by exploring and appreciating the most basic processes underlying body function, such as those driving cell growth, that we shall be able to tackle the root cause of the problem.

The hypothesis that the process of neurodegeneration results from an aberrant deleterious triggering of a previously normal, albeit unidentified, developmental process is not new (Butcher & Woolf, 1989). However, over the past two decades, empirical evidence has mounted for a link between the basal plate derived nuclei, their persistent sensitivity to trophic factors, and their vulnerability to neurodegeneration.

It is now possible, finally, to start putting these various pieces of the jigsaw together with reference to the novel T14 signalling system: in so doing we can appreciate a more dynamic picture of the neurodegenerative process and thereby gain insights for, at last, laying to rest the spectre of AD.