Dear Friends...

12 November, 2015
Dear Friends,
I am writing this letter, first, to express my appreciation for your support of Prana Biotechnology and, more generally, drug development aimed at preventing and treating this terrible disease called Alzheimer’s disease (AD). Second, I would like to take the opportunity to update you on how recent studies modelling AD, using human stem cell-derived neurons grown in 3D cultures, have dramatically enhanced and clarified our understanding of the pathogenic events underlying AD-related neurodegeneration. The past year of AD research has arguably been one of the most exciting in the last two decades. I say this in references to new revelations coming out of genetic studies of AD, as well as the insights regarding the etiology and pathogenic events underlying AD, emerging from our new model of the disease dubbed “Alzheimer’s-in-a-Dish”. We have developed this new model of AD using human stem cell-derived neural cultures grown in petri dishes in a gel that resembles the milieu of the brain. This is referred to as 3-D neural culture and we used it to recreate for the first time, the two major pathological hallmarks of AD - deposits of beta-amyloid protein, which appear as senile plaques (outside neurons), and twisted aggregates of tau proteins that manifest as neurofibrillary tangles (inside neurons). While those in the AD research field agree that it is the tangles and inflammation that kill neurons, heavy debate has raged for thirty years in the Alzheimer’s research community as to what initiates the tangles and deadly neurodegenerative cascade—the beta-amyloid or something else.
While our and other’s genetic studies of AD over the last three decades have strongly supported the notion that beta-amyloid acts as a trigger for tangle formation and neurodegeneration, evidence against this idea was suggested by two repeated findings. First, when the early-onset familial AD gene mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) were introduced into mice in attempts to create animal models for AD, plaques were observed, eventually leading to
neuroinflammation, cell death, and cognitive deficits. However, no tangles were produced. This suggested beta-amyloid does not lead to tangles - at least, in mice. Second, many anti-amyloid therapies failed in clinical trials. Now, Alzheimer’s-in-a-dish, using human (not mouse) neurons, has clearly shown that beta-amyloid is sufficient to lead directly to tangles (after ~9 weeks in culture). Furthermore, we showed that if you stop the deposition of beta-amyloid, you also stop the tangles. Regarding the numerous failed clinical trials targeting beta-amyloid, we now know that beta-amyloid accumulates 10-20 years before any cognitive symptoms of AD and that treating AD by only targeting amyloid in mid-late stage patients is too little-too late. Beta-amyloid deposition must be targeted as early as possible, preferably at the pre-dementia stage of the disease process. Recent discoveries in AD genetics have also strongly implicated neuroinflammation as the third pillar of AD pathology (in addition to beta-amyloid deposition (e.g. as senile plaques and neurofibrillary tangles). In 2008, we discovered the new AD gene, CD33, and in 2012, Decode (Iceland) discovered the AD gene, TREM2. We now know that these two genes play a major role in controlling neuroinflammation in AD. These are now serving as drug targets for regulating neuroinflammation in AD. This is particularly important in patients with mid-late
stage AD. The newest combined genetic, imaging, biomarker, and Alzheimer’s-in-a-Dish data now collectively illustrate a path for Alzheimer’s pathology in which first, beta-amyloid accumulates in the brain, decades before cognitive impairment. Beta-amyloid then triggers the production of tangles that kill neurons from within as well as neuro-inflammation, which kills more neurons. As increasing numbers of neurons die, there is more neuro-inflammation driven by microglial cells (regulated by the genes, CD33 and TREM2). Inflammation then drives even more plaques and tangles, and a vicious cycle ensues. We have been using Alzheimer’s-in-a-Dish to find drugs that will slow or halt plaque and tangle formation. Among those that are being tested is PBT2. Studies of PBT2 are still in progress and once confirmed, will be submitted for publication. So far, the preliminary findings show that PBT2 has the following effects in Alzheimer’s-in-a-Dish: 1. A trend in the direction of attenuation of the aggregation and fibrillization of the Abeta peptide into beta-amyloid, 2. significantly reduced tangle formation, and 3. significantly increased cell viability.
Once these results are confirmed, PBT2 would become the only compound tested in Alzheimer’s-in-a-Dish to achieve all three of these effects on AD pathology.
In closing, based on recent findings, I firmly believe, that beta-amyloid remains the best
target for preventing and treating AD, but this must be achieved in the earliest stages of the disease process. Based on the combined data, I continue to believe that PBT2 carries great potential for curbing plaque and tangle formation, while also enhancing neuronal cell viability as an AD therapeutic.
Sincerely yours,
Rudolph E. Tanzi, Ph.D.