Transcript of Live Discussion.

Unconventional Concept: NMDA receptor hypoactivity (NRHypo) can kill neurons.

In fact, NRHypo can cause neurodegenerative changes similar to those in Alzheimer's disease.

References: Olney JW, Wozniak DF, and Farber NB. Excitotoxic neurodegeneration in alzheimer's disease: New hypothesis and new therapeutic strategies, Archives of Neurology, Oct. 1997. Abstract

Corso TD, Sesma MA, Tenkova TI, Der TC, Wozniak DF, Farber NB, Olney JW. Multifocal brain damage induced by phencyclidine is augmented by pilocarpine, Brain Res 1997, 752: 1-14. Abstract

Q & A

NRHypo is a condition induced experimentally in animal brain by drugs that block NMDA receptors.

When NRHypo is induced in rat brain by NMDA antagonist drugs, this causes a neurodegenerative syndrome resembling that seen in AD.

Hypothesis: NRHypo is the missing link mechanism that can explain how neurodegenerative events are triggered in the AD brain.

Large to medium sized pyramidal and multipolar neurons are preferentially affected.

As illustrated in Fig. 1 the overall pattern of NRHypo neurodegeneration is very similar to the pattern that has been described in the AD brain by various researchers.

The posterior cingulate is the brain region most vulnerable to NRHypo degeneration (Fig. 2).

Although the posterior cingulate cortex has been relatively ignored by AD researchers, it is now known that this region:

• Is conspicuously affected early in the disease
  (Minoshima et al, Ann Neurol, 1997. Abstract)
• And shows extreme pathological changes and atrophy late in the disease (Insausti et al., 1993; Brun and Englund, 1981. Abstract).

It is roughly homologous to the perirhinal cortex in rat brain which is second only to the posterior cingulate in its sensitivity to NRHypo neurodegeneration (Fig. 3).

Other brain regions preferentially affected in both the AD brain and NRHypo model include portions of the isocortex (parietal, temporal; Fig. 4), as well as amygdaloid (Fig. 3), subicular, hippocampal and insular cortices.

• Same brain regions affected
• Same types of neurons affected
• Synaptic complexes are deleted
• Abnormal expression of HSP-72
• Tortuous cytoskeletal changes

Other parallels are currently under study

In "normal" aging (rats, mice & monkeys), the NMDA receptor system becomes markedly hypofunctional (Wenk et al., 1991; Tamaru et al., 1991; Gonzales et al., 1991; Magnusson and Cotman, 1993).

Thus, NRHypo is already present in the aging brain--this sets the stage for corticolimbic neurodegeneration.

Hypothesis: Difference between "normal" aging and AD is that compounding factors are present in AD that promote NRHypo. Candidates include amyloidosis, oxidative stress, defects in energy metabolism see Fig. 6).

Relevant Evidence: NRHypo is more severe in AD brain than in "normal" aging brain (Ulas and Cotman, 1997)

NRHypo degeneration is mediated by a complex multisynaptic circuit (Fig. 5)

Inhibition failure is key underlying principle

• Glutamate tonically activates NMDA receptors on GABAergic neurons
• Glu regulates inhibitory tone and ordinarily protects the brain against its own self destructive potential
• Removing this inhibitory mechanism unleashes excitotoxic forces that destroy vulnerable neurons in the circuit

Everyone Else: Muscarinic receptors are hypoactive in AD; we need drugs to stimulate these receptors.

Compromise:

• Cholinergic hyperactivity occurs early in AD;
• Death (hypofunction) of cholinergic neurons occurs late

Evidence from both MR spectroscopy studies and autopsy studies support the compromise view.

FACT: NRHypo can cause AD-like neurodegeneration.

FACT: NRHypo is present in the "normal" aging brain and is more pronounced in the AD brain. HYPOTHESIS: NRHypo may be promoted by factors present in AD (e.g., oxidative stress or amyloidosis). Thus, NRHypo may be the missing link mechanism to explain AD neurodegeneration. (Fig. 6)

FACT: We know how to prevent NRHypo neurodegeneration (Table 1).

HYPOTHESIS: Some of these agents may prove to be beneficial in the treatment of AD.

Q & A

Question from Dmitry Tokarev
Olney et al. hypothesis is very interesting. I'm amateur in this field. My question is about changes between NRhypo and neuroendocrine correlation in AD. Probably NRhypo would have to affect hypothalamic GnRH and CRF. What is your opinion?

Reply from John Olney:
We do not have any specific data on neuroendocrine effects associated with the NRHypo state. But it would be possible to treat adult rats with an NMDA antagonist to produce widespread corticolimbic neurodegeneration and determine whether the residual deficit syndrome includes disturbances in GnRH and CRF.

The most reliable way to produce the full pattern of widespread neurodegeneration is to administer a high dose of PCP plus a low dose of pilocarpine. This is described in the following manuscript: Corso TD, Sesma MA, Tenkova TI, Der TC, Wozniak DF, Farber NB, Olney, JW. "Multifocal brain damage induced by phencyclidine is augmented by pilocarpine." Brain Res. 752, 1-14, 1997.

Transcript of Live Discussion.