Posted 23 March 2001

Interviewed by Chris Weihl

ARF: What is the hypothesis driving research in your lab?

Gandy: We are investigating the role of signal transduction in regulating b amyloid generation; both the possibility (1) that changes in signalling contribute to disease-related changes in b amyloid metabolism and (2) that pharmacological modulation of specific signalling pathways can be employed for therapeutic modulation of b amyloid metabolism.

ARF: How do you account for the anatomical pattern and cellular specificity in the progression of AD?

Gandy: Generally, I wave my hands. I'd predict that those areas have particularly critical levels of local amyloid-enhancing or amyloid-clearing molecules in the extracellular matrix that are yet to be identified, but I can't prove that. The idea of propagation along established projection pathways is intriguing and may be provable in plaque-forming transgenic mice.

ARF: Describe the cascade of events that lead to AD pathogenesis?

Gandy: Amyloid starts and causes the disease. Tau changes are related but secondary. I recognize that this is difficult to support based on their differential neuroanatomy, but I would suspect that neurons are different in their ability to form tangles or to die in response to amyloid. The current notion of "misfolded, toxic, but not histochemically visible" amyloid could also be playing a role but it is maddeningly difficult to study in vivo.

I am convinced that AD is an organ-specific amyloidosis, like the visceral and peripheral nerve amyloidoses. I see no evidence that neurofibrillary tangles in particular or neurodegeneration in general can cause typical Alzheimer amyloidosis. The recent data linking b amyloid to tau phosphorylation via cdk5 provide a very attractive way to link the two structures.

I don't understand how neurons and synapses die in AD, but, frankly, I don't spend much time thinking about it: I'd rather invest in preventing, halting or reversing the amyloidosis. I'm convinced that the disease must be prevented or halted early, and that the way to do that is to attack the amyloidosis.

ARF: What key bits of evidence are still missing that would convince you of the correctness of your hypothesis?

Gandy: Human clinical prevention and treatment trials.

ARF: Are there existing data that contradict your hypothesis?

Gandy: The most troublesome data are from plaque-forming mice with such heavy amyloid burdens and so little neurodegeneration. However, it is most important to prove that amyloid causes behavioral changes, and strong data along those lines were recently reported by David Westaway, Peter Hyslop, Paul Fraser and colleagues (Janus et al., Nature, 2000).

ARF: What evidence would convince you that your hypothesis is incorrect?

Gandy: If an effective anti-amyloid compound is administered to preclinical individuals with APP or PS mutations, and they go on to develop an amyloid-free dementing illness.

ARF: What therapeutic strategies will be the most promising?

Gandy: I still prefer prevention, with gonadal hormone replacement still promising, in my opinion. We believe that these compounds protect against AD by lowering brain levels of b amyloid, so this is a form of b/gamma secretase modulation. Ralph Martins and his colleagues in Perth have recently provided in vivo evidence for this in humans.

I like anti-aggregation agents, the betabloc vaccine, and b- and gamma-secretase inhibitors. The anti-aggregant approach is particularly attractive since this is a direct antagonist of the pathogenic step: the conversion of soluble b amyloid into aggregated b amyloid.

Since I prefer prevention, I'll have to wait for safety and efficacy data to choose which would be most reasonable for asymptomatic people, but I'd like to think that some routine pill...or some routine immunization...will be a usable prophylactic.

ARF: Will we be able to cure AD?

Gandy: In an ideal world, I'd probably focus on prevention. However, it is difficult, expensive and protracted to do primary prevention trials in normal people. I hope that we will be able to succeed with the same range of anti-amyloid approaches if we intervene at the very earliest sign of AD detectable with neuroimaging or psychometrics, but I'm not convinced that the "horse isn't already out of the barn". The best hope has come from mouse models of Huntington Disease where it is clear that preventing the ongoing synthesis of huntingtin protein permits the brain to recover.

ARF: Where are the most exciting research opportunities for young investigators such as myself?

Gandy: The greatest need is in preclinical/early diagnosis so that these terrific anti-amyloid compounds can get going! A pharmacogenomic approach might be envisioned in which a particular profile of polymorphisms could accurately predict who was at highest risk as well as what the age at onset would be and which drugs would be most effective and which ineffective. This is now possible with genomic profiling of tumors, e.g. it would be terrific to be able to get to a similar point in AD.

As you might expect, though, the greatest need is also an enormous challenge, so if one were to undertake such a program, some safer projects would also need to be in the mix. One of the biggest mistakes for young investigators is to get into highly speculative and/or highly competitive areas early on in their careers without having "safety projects" to keep themselves productive and funded!

Selected Readings, with comments by Dr. Gandy

Beginning in 1986 (and prompted by Dmitry Goldgaber's localization of the amyloid precursor to chromosome 21), an Alzheimer's Unit was developed together with Paul Greengard, focusing on identifying ways to manipulate the metabolism of Alzheimer's A-b. Because protein phosphorylation is such a ubiquitous regulatory mechanism, we began by asking the simple question, "Does protein phosphorylation regulate metabolism of Alzheimer's A-b?" By the early 1990's, we were able to answer that question in the affirmative with a series of papers showing that intracellular second messengers and extracellular neurotransmitters and hormones could modulate generation of new A-b molecules:

Buxbaum JD, Gandy SE, Cicchetti P, Ehrlich ME, Czernik AJ, Fracasso RP, Ramabhadran TV, Unterbeck AJ, Greengard P. Processing of Alzheimer /A4 amyloid precursor protein: modulation by agents that regulate protein phosphorylation. Proc Natl Acad Sci U S A. 1990 Aug;87(15):6003-6. Abstract

Caporaso GL, Gandy SE, Buxbaum JD, Ramabhadran TV, Greengard P. Protein phosphorylation regulates secretion of Alzheimer /A4 amyloid precursor protein. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3055-9. Abstract

Buxbaum JD, Oishi M, Chen HI, Pinkas-Kramarski R, Jaffe EA, Gandy SE, Greengard P. Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer /A4 amyloid protein precursor.Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10075-8. Abstract

Jaffe AB, Toran-Allerand CD, Greengard P, Gandy SE. Estrogen regulates metabolism of Alzheimer amyloid precursor protein. J Biol Chem. 1994 May 6;269(18):13065-8. Abstract

Xu H, Gouras GK, Greenfield JP, Vincent B, Naslund J, Mazzarelli L, Fried G, Jovanovic JN, Seeger M, Relkin NR, Liao F, Checler F, Buxbaum JD, Chait BT, Thinakaran G, Sisodia SS, Wang R, Greengard P, Gandy S. Estrogen reduces neuronal generation of Alzheimer -amyloid peptides. Nat Med. 1998 Apr;4(4):447-51. Abstract

Petanceska SS, Gandy S. The phosphatidylinositol 3-kinase inhibitor wortmannin alters the metabolism of the Alzheimer's amyloid precursor protein. J Neurochem. 1999 Dec;73(6):2316-20. Abstract

Proof-of-concept studies have demonstrated that some of these regulatory mechanisms can be exploited to lower A-b levels in the brains of living animals:

Petanceska SS, Nagy V, Frail D, Gandy S. Ovariectomy and 17beta-estradiol modulate the levels of Alzheimer's amyloid peptides in brain. Neurology. 2000 Jun 27;54(12):2212-7. Abstract

Haugabook SJ, Le T, Yager D, Zenk B, Healy BM, Eckman EA, Prada C, Younkin L, Murphy P, Pinnix I, Onstead L, Sambamurti K, Golde TE, Dickson D, Younkin SG, Eckman CB. Reduction of A- accumulation in the Tg2576 animal model of Alzheimer's disease after oral administration of the phosphatidylinositol kinase inhibitor wortmannin. FASEB J. 2001 Jan;15(1):16-18. Abstract

Recent work in this area indicates that gonadal hormones are likely to be important regulators of A-b metabolism in humans:

Gandy S, Almeida OP, Fonte J, Lim D, Martins G, Waterrus A, Corica T, Spry N, Flicker L, Martins RN. Plasma Alzheimer's amyloid-b peptide rises during hormone deprivation. JAMA 2001, in press.

The ongoing effort to elucidate the molecular basis for "regulated cleavage" is demonstrated in these representative papers:

Xu H, Greengard P, Gandy S. Regulated formation of Golgi secretory vesicles containing Alzheimer -amyloid precursor protein. J Biol Chem. 1995 Oct 6;270(40):23243-5. Abstract

Xu H, Sweeney D, Wang R, Thinakaran G, Lo AC, Sisodia SS, Greengard P, Gandy S. Generation of Alzheimer -amyloid protein in the trans-Golgi network in the apparent absence of vesicle formation. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3748-52. Abstract

Review
Gandy S. Neurohormonal signaling pathways and the regulation of Alzheimer beta-amyloid precursor metabolism. Trends Endocrinol Metab. 1999 Sep;10(7):273-279. Abstract