After solanezumab – where does Alzheimer’s disease research go from here?

After solanezumab – where does Alzheimer’s disease research go from here?

Jeremy Taylor

[See all essays on this Hot Topic]
A few weeks ago, pharmaceutical giant Eli Lilly announced that their latest Phase II trial for a drug named solanezumab, which is designed to flush beta-amyloid protein out of the brain and thereby ameliorate the symptoms of Alzheimer’s disease, had been a failure. This is a huge blow to conventional Alzheimer’s disease research because it comes on the back of more than a decade’s-worth of failed trials for drugs that either interfere with the chain of enzymatic reactions that make beta-amyloid, or remove it from the brain. Most of these trials were done with patients who were already in the advanced stage of the disease, and it may be too much to expect any treatment to be successful in the face of such widespread neuronal degeneration. This has led to research initiatives to identify cohorts of patients either in much earlier stages of Alzheimer’s disease, or of young, symptomless age but related to individuals who had succumbed to the familial, early-onset form of the disease. This solanezumab trial used patients with only mild cognitive impairment and yet it showed no statistical improvement in cognition in treated patients over placebo controls.

What does this failure mean for Alzheimer’s disease research? In what direction should it now go? Should the “amyloid hypothesis” now be abandoned? The overwhelming consensus in Alzheimer’s disease research has held it to be self-evidential that the tell-tale plaques of beta-amyloid protein between neurons and hyper-phosphorylated tau protein within neurons are not only pathological proof of Alzheimer’s disease but are the toxins that cause the disease in the first place. But it is becoming clear to anyone willing to acknowledge the evidence that this may be very far from the full story. Very recently, the 90+ study, run by the University of California at Irvine, produced evidence that many of our oldest-old die with substantial Alzheimer’s pathology in their brains but with fully-functioning preserved cognitive powers. It is the latest in a string of similar observations that dates back to Alzheimer research pioneers Bob Katzman and Bob Terry, at UCSD, in the 1980s and 90s. They similarly identified a cohort of the elderly who had died at a mean age of 85 years with intact cognition in brains riddled with amyloid, and, conversely, individuals who were diagnosed with Alzheimer’s disease who were found, on autopsy, to lack significant amyloid and tau pathology. Why were some brains more resilient to amyloid pathology than others? Katzmann and Terry thought it might have something to do with cognitive reserve. Resilient brains tended to be bigger brains and belonged to individuals in the upper centiles of intellectual performance. Maybe they lost synapses to amyloid but just had better brains, with more synapses, and, consequently, had more to lose and took longer to lose it? Their decline into dementia was just slower. This theme was returned to in 2004 by Nikolaos Scarmeas and Yaakov Stern in a paper titled “Cognitive Reserve: Implications for Diagnosis and Prevention of Alzheimer’s Disease.”

However, importantly, Bob Terry won the Potemkin neuroscience prize back in 1988 for counting cortical synapses from normally aged and Alzheimer’s diseased brains and showing that there were only weak correlations between density of plaques and tangles and psychometric tests of intelligence but much stronger correlations between those tests and synapse density. He further showed that loss of synapses was independent of the presence of amyloid in diffuse plaques and concluded that amyloid deposition was the result of synapse pathology, not the cause. Alzheimer’s disease was a disease of synapses, not of amyloid.

Several respected science communicators, including George Perry of the University of Texas, have accused the so-called amyloid lobby of persevering with amyloid and tau for no better reason than the fact that, ever since the days of the eponymous pioneer of neurodegenerative brain research Alois Alzheimer, amyloid plaques and tau tangles have been visible in brains via microscopy or medical imaging. Nevertheless, the amyloid lobby continues to test their hypothesis to destruction in trials still underway which administer anti-amyloid drugs to individuals thought to be at risk of Alzheimer’s disease well before any cognitive decline registers itself. They are trying to intervene at ground zero. But, in the search for the initial pathology of Alzheimer’s disease, will we find that beta-amyloid and tau are even relevant? What other processes and agents deserve much greater attention? What really causes these brains to start dying in a more profound and accelerated way than can be laid at the door of the normal ageing process?

The more I read about research into Alzheimer’s disease the more I am reminded of the old Indian parable of the blind men and the elephant. Twelve blind men are stood around the beast at intervals and are requested to describe and identify it based only on what they can make of the small portion of its anatomy that lies within their hands’ grasp. Of course, none of them can take on board what the others are feeling, there is no overall picture, and so they end up in total disagreement, and in no little ignorance as to what the beast actually looks like.

Let us think about amyloid a little further. We know it is present in neurons because it has a clearly defined evolved function in regulating transmission of impulses along neuronal networks – supporting long term potentiation, which is involved in the storage of memory at synapses, and regulating over-excitation within neural networks. And it is commonly asserted that the slightly longer-chain Aß-42 molecules are more toxic than Aß-40 and only when they form into certain types of oligomers. Rebecca Rosen et al, in a paper titled “Comparative Pathobiology of Aβ and the Unique Susceptibility of Humans to Alzheimer’s Disease”, question why it is that humans appear uniquely susceptible to the neurodegeneration and dementia of Alzheimer’s disease despite the fact that all primates deposit copious Aß in senile plaques and accumulate cerebral amyloid-β angiopathy as they grow old. And despite the fact that the amino-acid sequence of beta-amyloid is identical in all primates – including humans – so far studied. Also, transgenic rodent models engineered to overproduce human-sequence beta-amyloid develop profuse senile plaques and cerebral amyloid-β angiopathy, but they do not have substantial AD-like neuronal cell loss, neurofibrillary tangles, and profound memory impairment. They conclude with the possibility that the only between-species differences they could find – subtle differences in the tertiary structure of beta-amyloid – the three-dimensional geometry of protein chain folding – might explain why beta-amyloid is toxic to humans but not to any other species.

But dissecting beta-amyloid in ever increasing detail like this still leaves us with the fundamental question: Is it the accumulation of beta-amyloid into plaques, and the subsequent formation of hyper-phosphorylated tau protein tangles inside neurons, that are the initiating events for Alzheimer’s disease, or not? Here it is important to distinguish between familial Alzheimer’s disease and sporadic Alzheimer’s disease. The former represents less than 5% of all AD cases and is caused by well-known mutations to genes like APP or the presenilins, which are involved in the chain of enzymatic reactions that form beta-amyloid. If you bear any of these mutations you will succumb to the disease – it is deterministic. The vast majority of cases of Alzheimer’s are the sporadic form which tells us that, whatever genes might be involved, the environment is a major factor. Central to this observation is the establishment, over the last 20 or 30 years, that no satisfactory answer to the riddle of Alzheimer’s disease will ever be found unless we take the role of the immune system, and the inflammation caused by innate immunity, into account.

A number of researchers hold that, while inflammation is an important factor in Alzheimer’s disease, it is secondary to the production of amyloid and tau in the brain. That it is the production of amyloid and tau that elicits inflammation. But it looks increasingly likely that the opposite is true.

Back in the 1980s, Sue Griffin used Down syndrome to investigate Alzheimer’s disease. Down syndrome brains accumulate amyloid at premature age because of the extra copy of chromosome 21 on which the APP gene sits. Nevertheless, Griffin showed that Down syndrome brains produce large amounts of the inflammatory cytokine interleukin-1 (IL-1) many years before plaque formation, suggesting that stressed neurons lead to inflammation and innate immune activity in the brain, production of inflammatory markers, and eventually excess amyloid and tau.

The importance of innate immune system activity in the brain was heavily underscored a few years ago by 3 genome-wide association studies which found no effect for the main genes involved in the pathways that form beta-amyloid and tau, but were dominated by genes involved in the immune system.

Research by Clive Holmes and Hugh Perry in Southampton has established that peripheral infection can send signals to the brain which accelerate immune activity there, heighten the symptoms of Alzheimer’s disease, lead to cognitive deficits, and prime microglia – the brain’s immune cells and the equivalent to macrophages – so that they are capable of attacking and damaging neurons. Their research has been borne out in a mouse model by Irene Knuesel and Dimitrij Krstic which mimicked peripheral viral infections and showed increases in inflammatory mechanisms in the brain, priming of microglia, degenerating neurons and only then production of amyloid and tau.

What key events occur at the synapse years before any signs of cognitive impairment begin to emerge? Some researchers believe that beta-amyloid is the prime culprit in these early days but their work is countered by fascinating evolution-minded research by Beth Stevens at Harvard and her former colleague Ben Barres. Picking up from those earlier conclusions that synapse loss correlates better than amyloid with AD cognitive symptomatology, Hong et al (co-authors include Stevens, Barres and Dennis Selkoe) show in a series of mouse models that another major part of the innate immune system – complement – together with immune cells called microglia – are heavily involved in initiating events at the synapse that precede amyloid deposition. The initiating protein of the complement cascade – C1q – is first associated with synapses and experiments that inhibit it show that C1q is necessary for any toxic effect of beta-amyloid on synapse function and long-term potentiation in the hippocampus. Similarly, when the complement receptor CR3 is silenced on microglia they stop phagocytically engulfing synaptic material.

Stevens, Barres, and their associates remind us that evolution has co-opted the complement cascade as the mechanism by which neural networks are adaptively pruned during adolescence and brain development and as a response to later learning. C1q paints synapses that are scheduled for demolition and reacts with proteins on these cell surfaces to form the complement protein C3 which is recognised by CR3 on microglia which then steam in for the kill. Most of the body’s cells are protected against this unwanted intrusion by complement because they are bristling with complement inhibitors. Neurons are the exception. They lack these inhibitors for the very reason that they have to be open to complement attack otherwise selective pruning could never occur. It is an Achilles heel which shows up in late-onset Alzheimer’s disease because Stevens, Barres et al believe the roots of Alzheimer’s disease are laid when this evolved method for synaptic pruning is re-awakened maladaptively in later life. It may be, they say, that soluble beta-amyloid has a role here in that it could bind to synapses and weaken them, providing the complement cascade with a signal for elimination.

Not surprisingly, in the light of all this, a group of scientists in the UK, led by Prof. Paul Morgan of Cardiff University, have published research which suggests that complement proteins can provide reliable early markers for onset of Alzheimer’s disease, specifically to allow physicians to distinguish between individuals with mild cognitive impairment who will convert to Alzheimer’s from those who will not.

The gene that we know for sure increases your chance of contracting Alzheimer’s by up to ten times is a variant of APOE – epsilon 4. And while APOE is involved with a number of processes in the brain that also involve beta-amyloid, there are a number of other Alzheimer’s producing processes in which APOE4 acts independently. Because it is involved in cholesterol transport, APOE is vital for maintaining neurons and their synapses, and the epsilon 4 variant impairs this. Carriers of APOE4 have thinner entorhinal cortices and hippocampi, and APOE4 frequently increases inflammation in the brain and primes toxic microglia. It is known that another variant of APOE – epsilon 2, is protective of Alzheimer’s disease and it was assumed that APOE2 carriers with somewhat preserved cognition would consequently be found to have been relatively free of amyloid pathology. But the group who run the 90+ Study at UC Irvine have discovered that while, in the oldest-old, the presence of APOE2 was associated with a somewhat reduced risk of dementia, it was also, paradoxically, associated with increased AD neuropathology. Therefore, they conclude, oldest-old APOE2 carriers may have some mechanism that contributes to the maintenance of cognition independently of the formation of AD pathology and specifically note that APOE2 carriers have preserved synaptic function.

It is too early to abandon the so-called amyloid hypothesis. Soluble beta-amyloid or oligomers of beta-amyloid 42, and aberrant tau protein, are clearly neurotoxic and important. But they may not be instigatory. The amyloid hypothesis, at the very least, is undergoing substantial revision as the long history of blinkered over-attention to tell-tale plaques and tangles gives way to the nuances of environmental factors and innate immune responses in brain and body and the important distinctions between early-onset familial AD and the majority late-onset sporadic AD come home to roost. In the following two commentaries, Caleb Finch draws attention to the possible role of smoking and atmospheric pollution, while Robert Moir rehabilitates the amyloid “bad boy” by showing its evolved importance as a potent antimicrobial – thereby opening the door to a possible infection etiology for Alzheimer’s disease. 35 million people world-wide are living in the twilight world of Alzheimer’s disease without the ghost of a cure in sight, despite the investment of many billions of dollars. We owe it to these Alzheimer’s sufferers – in the US alone a new case gets diagnosed every 68 seconds – to broaden the church of AD research in such ways – and allow this new research to present effective targets for treatment. It is long overdue.

Is Alzheimer’s disease related to heterochronic changes in the brain during human evolution?

Is Alzheimer’s disease related to heterochronic changes in the brain during human evolution?

Enric Bufill

Enric Bufill MD Ph D
Hospital Universitari de Vic, c.Francesc Pla 1, 08500, Barcelona Spain.

 

 

Alzheimer’s disease (AD), the most common cause of dementia, is a complex disease associated with advanced age whose causes are still not fully known. AD is very common in humans and extremely uncommon in other mammals, which suggests a relationship between the disease and genetic, functional and structural changes that have taken place throughout the evolution of the human brain (1).

AD is characterized by deposits of abnormal peptides in the brain. Neurofibrillary tangles (NF) made up of the aggregation of hyperphosphorylated tau protein are found in the interior of the neuron, where they form double helicoidal filaments that distort the neuronal cytoskeleton. Neuritic plaques on the other hand, are made up of the accumulation of beta amyloid peptides (Aβ), fragments of a transmembrane protein called amyloid precursor protein or APP, found in the extracellular space.

Many researchers support the hypothesis that amyloid plaques, as well as tangles to lesser extent, are neurotoxic and lead to neuronal death (the amyloid cascade hypothesis) (2). The amyloid cascade hypothesis has led to a line of therapies that promote plaque clearance or prevention of plaque formation. However, a relatively high percentage of elderly people develop Aβ deposits without developing cognitive deterioration.

Recent studies show that Aβ peptide has antimicrobial properties, and that the absence of this peptide can lead to increased vulnerability to infection. Although the immune system has limited access to the central nervous system, it could combat invading pathogens by means of antimicrobial peptides, including Aβ. An abnormal accumulation of this peptide could be caused by persistent subacute infection in the central nervous system, by transitory infections capable of triggering self-perpetuating immune responses, or by an excess of noninfectious factors like trauma, ischemia, toxins or anesthetics (3,4). Some researchers posit that Aβ is an antioxidant released as a compensatory response to oxidative stress (5).

In any case, the generation of β amyloid peptide may have an adaptive function in its initial phases. Instead of being the cause of AD, it could be initially a defense mechanism. Furthermore, drugs that reduce the production of Aβ, prevent its aggregation or promote its clearance have not been found to be effective in the phase 3 studies carried out to date (6,7).

Heterochronic changes during human brain evolution and AD

In the brain, cerebral glucose metabolism is mainly used to supply energy by means of oxidative phosphorylation. However, when energy use exceeds the energy that can be made in this way, a non-oxidative route for the metabolism of glucose, aerobic glycolysis, provides additional energy.

In the brain, aerobic glycolysis is related to activity-dependent synaptic changes in adults. Aerobic glycolysis seems to play a critical role in synaptic activity and synaptic plasticity (8).

Aerobic glycolysis in the human brain is significantly elevated in cortical areas related to cognitive functions which have undergone major modifications during the evolution of human species, such the dorsolateral prefrontal cortex and the brain’s default mode network (BDMN) related to the coordination of the activity among different brain’s regions and to autobiographical memory and planning (1).

Aerobic glycolysis is correlated with the expression of genes that are active at younger ages, especially those related to synaptic formation and growth (9). BDMN neurons retain juvenile characteristics into adulthood such as incomplete myelination and elevated synaptic plasticity and activity (neuronal and transcriptional neoteny) (8,9).

The distribution of the extracellular Aβ plaques found in AD coincides almost exactly with the BDMN, which suggests that elevated synaptic plasticity could predispose to developing the deposits of abnormal peptides characteristic of AD.

Multiple studies have shown that oxidative stress is associated with AD, and that it is one of the first events that occurs in the development of the disease. The increase in aerobic metabolism in human neurons that retain juvenile characteristics into adulthood can make these neurons more likely to exhibit greater oxidative stress with age. The retention of juvenile characteristics such as increased synaptic plasticity in certain neurons of the human brain can make them more vulnerable to the multiple factors that can trigger the onset of AD (10). Oxidative stress can also induce epigenetic changes reducing the expression of certain genes, including those related to synaptic plasticity (11).

If Aβ deposits were initially a defense against oxidative stress, preventing their accumulation in the first stages of the disease could have harmful consequences even the acceleration of the disease. In fact, a trial using an agent that prevented the formation of Aβ had to be terminated early due to the experimental group’s declining at a faster rate than the placebo group (12).

Therefore, given the data we currently have, instead of concentrating on preventing amyloid formation, it might be better to focus efforts on different lines of work, such as longitudinal studies on aerobic glycolysis in BDMN correlated with genetic and environmental factors which may be related to AD, the study of epigenetic changes induced by oxidative stress and other environmental factors etc. The study of changes in aerobic glycolysis in BDMN could also be helpful in pharmacological trials.

Trials with synaptic plasticity’s modulators such as reelin, which have already given good results in transgenic mice, may be an interesting option in the future (13).

Editors Note.

The human brain has a formidable appetite for glucose and never more so than when it is developing. An infant’s brain is estimated to consume more than 40% of the body’s basal metabolic rate. Most of the glucose is oxidised in the production of ATP but this process is augmented by non-oxidative metabolism of glucose even when there is abundant oxygen to hand. This is termed aerobic glycolysis (AG) and accounts for in excess of 10% of the glucose consumed by the brain. This excess brain glucose consumption is also found in cancer where it helps to support cell proliferation. Research suggests AG increases in childhood and is synonymous with high rates of synaptic formation and growth, and later synaptic remodeling, and AG correlates with the persistence of gene expression associated with infancy (transcriptional neoteny). AG also identifies regions of the brain that are most vulnerable to beta-amyloid deposition in Alzheimer’s disease.

(1). “Aerobic glycolysis in the human brain is associated with development and neotenous gene expression.” Goyal et al, Cell Metab. 2014 Jan 7: 19 (1): pp 49-57.

REFERENCES

  1. Bufill E, Agustí J, Blesa R.2011. Human neoteny revisited: The case of synaptic plasticity. Am J Hum Biol 23:729-739.
  2. Glass DJ, Arnold SE.2016. Why are humans vulnerable to Alzheimer’s disease ? In Alvergne A, Jenkinson C, Faurie C eds. Evolutionary thinking in medicine.Springer Switzerland pp329-345.
  3. Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B, Burton MA, Goldstein LE, Duong S, Tanzi RE, Moir RE. 2010. The Alzheimer’s disease associated amyloid-β protein is an antimicrobial peptide. PLOsoNE, 5: e9505.
  4. Bufill E, Bartés A, Moral A, Casadevall T, Codinachs M, Zapater E, Rovira JC, Roura P, Oliva R, Blesa R. 2009. Factores genéticos y ambientales que pueden influir en la forma senil de la enfermedad de Alzheimer: estudio de casos y controles anidado. Neurologia 24 (2): 108-112.
  5. Castellani RJ, H-g Lee, Nunomura A, Perry G, Smith MA. 2006. Neuropathology of Alzheimer disease: pathognomonic but not pathogenic. Acta Neuropathol (Berl) 111(6): 503-509.
  6. Salomone S, Caraci F, Leggio GM, Fedorova J, Drago F. 2012. New pharmacological strategies for treatment of Alzheimer’s disease: focus on disease modifying drugs. Br J Clin Pharmacol. 73: 504-517.
  7. Sperling RA, Jack CR, Black SE, Frosh MP, Greenberg SM, Hyman BT, Scheltens P, Carrillo MC, Thies W, Bednar MM, Black RS, Brashear HR, Grundman R, Siemers ER, Feldman HH, Schindler RJ. 2011. Amyloid –related imaging abnormalities in amyloid-modifying trials: Recommendations from the Alzheimer ‘s Association Research Roundtable Workgroup. Alzheimers Dement. 7: 367-385.
  8. Vaishnavi SN, Vlassenko AG, Rundle M, Snyder MA, Mintun MA, Raichle ME. 2010. Regional aerobic glycolysis in the human brain. Proc Natl Acad Sci USA 107: 17757-17762.
  9. Goyal MS, Hawrylycz M, Miller JA, Snyder AZ, Raichle ME. 2014. Aerobic glycolysis in the human brain is associated with development of neotenous gene expression. Cell Metabolism 19: 49-57.
  10. Bufill E, Blesa R, Agustí J. 2013. Alzheimer’s disease: an evolutionary approach. Journal of Anthropological sci 91: 131-157.
  11. Bowling A, Mutisya E, Walker L, Price D, Cork L, Beal M. 1993. Age-dependent impairment of mitochondrial function in primate brain. J Neurochem60: 1964-1967.
  12. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, He F, Sun X, Thomas RG, Aisen PS, Siemers E, Sethuraman G, Mohs R. 2013. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. New Engl J Med369 (4). 341-350.
  13. Pujadas L, Rossi D, Andres R, Teixeira CM, Serra-Vidal B, Parcerisas A, Maldonado R, Giralt R, Carulla N, Soriano E. 2014. Nature commun 5: 34-43.
Environmental Smoke in Alzheimer’s Disease

Environmental Smoke in Alzheimer’s Disease

Caleb E. Finch

Caleb E. Finch

Leonard Davis School of Gerontology and Dornsife College, University of Southern California, Los Angeles CA

 

 

Environmental influences on Alzheimer’s disease (AD) are under appreciated. The 25-year search for AD genes has clearly shown that dominant familial genes for early AD account for a small minority of cases less than 5% (Tanzi 2013). The largest common risk factor is the APOE4 allele which may account for another 15-20% of cases, mainly in women (Finch and Shams 2016). Human E4 carriers and mouse AD models show increased levels of the amyloid deposits, with female excess (Barnes 2005; Cacciottolo et al. 2016a). Major efforts continue to find new gene risk factors, which are generally rarer and of lower risk than ApoE4 (Tanzi 2013).

Tobacco smoking is also recognized as an environmental risk factor for AD by epidemiological studies: a meta-analysis of 23 prospective studies attributed 11% of later onset AD to smoking (Barnes and Yaffee 2011). Correspondingly, an AD mouse showed increased brain amyloid from short term tobacco smoke (Moreno-Gonzalez et al. 2013).

A new, but familar smoke may also be relevant. Automotive traffic derived air pollution (TRAP) is associated with increased dementia risk (Oudin et al 2016; Jung et al 2015). We extended these findings with the WHIMS cohort, in which older women residing in zones with PM2.5 from TRAP above the EPA standard of 12 ug/m3 had a 70% higher risk of dementia. Moreover, apoE4 carriers had up to 4-fold higher risk. At a population level, about 20% of dementia may be attributable to excess TRAP exposure. Correspondingly in an experimental model for exposure to TRAP, mice carrying human FAD genes in combination with human ApoE4 had higher brain amyloid than E3FAD mice (Cacciottolo et al. 2016b). Thus chronic inhalation of carbonaceous air particulates from fossil fuels or leaf tobacco show a similar magnitude of risk for AD (10-20%), and similar amyloidogenic responses of mouse models.

I suggest that these findings may guide the selection of AD patients or those at risk in future clinical trial. While the apoE genotype is under consideration in AD drug trials, there has been no mention of tobacco smoking or exposure to air pollution. The Alzheimer field recognizes the huge complexity of processes in AF that begin decades before clinical symptoms. We may need to expand thinking further with gene-environmental interactions. Lastly, I note that global human exposure to toxic carbonaceous particles from tobacco or fossil fuels is very recent, within 5-10 generations. Given the apparent absence of severe AD-like neurodegeneration in great apes (Finch and Austad 2015), one may ask: is AD a modern disease in association with these evolutionarily novel toxins?

Acknowledgements: I am grateful for support by the Cure Alzheimer’s Fund and the NIH (R01 AG051521; R21-AG040683). As a founder of Acumen Pharmaceuticals, I have received no support for these studies or any input in writing this essay.

References

Barnes LL, Wilson RS, Bienias JL, Schneider JA, Evans DA, Bennett DA.et al. .2005. Sex differences in the clinical manifestations of Alzheimer disease pathology. Arch. Gen. Psychiatry. 62, 685–691.

 

Barnes DE, Yaffe K. 2011. The projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol. 10:819-28.

Cacciottolo M, Christensen A, Moser A, Liu J, Pike CJ, Sullivan PM, Morgan TE, Finch CE. 2016. The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer‘s Disease of humans and mice. Neurobiol Aging, 37:47-57.

 

Cacciottolo M, Wang X, Driscoll I, Woodward N, Saffari A, Reyes J, Serre ML, Vizuete W, Sioutas C, Morgan TE, Gatz M, Chui HC, Shumaker SA, Resnick SM, Espeland MA, Finch CE, Chen JC. 2016. Particulate air pollutants, APOE alleles, and their contributions to cognitive impairment in older women and to amyloidogenesis in experimental models. Transl Psychiatr. in press.

Finch CE, Austad SN. 2015. Commentary: is Alzheimer’s disease uniquely human?Neurobiol Aging. 36:553-555.

 

Finch CE, Shams S. 2016. ApoE and sex bias in cerebrovascular aging of men and mice. TiNS 39:625-37.

 

Jung CR, Lin YT, Hwang BF. 2015. Ozone, particulate matter, and newly diagnosed

Alzheimer’s disease: a population-based cohort study in Taiwan. J Alzheimers Dis. 44:573-84.

 

Oudin A, Forsberg B, Adolfsson AN, Lind N, Modig L, Nordin M, Nordin S,

Adolfsson R, Nilsson LG. 2016. Traffic-Related Air Pollution and Dementia Incidence in Northern Sweden: A Longitudinal Study. Environ Health Perspect. 124:306-12.

 

Tanzi RE. 2013. A brief history of Alzheimer’s disease gene discovery. 33 Suppl 1:S5-13.

The Aβ story: rehabilitation of a bad boy

The Aβ story: rehabilitation of a bad boy

Robert D. Moir

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Robert D. Moir

Genetics and Aging Research Unit, Mass General Institute for Neurodegenerative Disease; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA

 

 

 

Deposition of amyloid-β peptide (Aβ) as β-amyloid plaques is the hallmark pathology for Alzheimer’s disease (AD). For over 30 years therapeutic strategies to treat AD have been guided by the dominant model of Aβ amyloidosis known as the amyloid cascade hypothesis. The hypothesis posits that cerebral accumulation of aggregated Aβ in the forms of β-amyloid plaques drives a neurodegenerative cascade that leads to widespread neuronal death. Despite overwhelming genetic and biochemical data supporting Aβ’s central role in AD, a growing number of researchers have begun to question if the amyloid hypothesis is valid. This skepticism has been fueled, in large part, by the failure of over 400 clinical trials of AD drugs, most of which target Aβ. This record of failures may well qualify as modern medicines worst performance ever. My laboratory has spent the last decade exploring an almost universally ignored aspect of Aβ – what normal physiological role does the peptide play in the brain? Our investigations have revealed some surprising, and we believe, paradigm-shifting findings about this ancient and ubiquitous peptide. Our interpretation of these findings suggest the problem may lay not with the amyloid hypothesis, but rather, with assumptions about Aβ that have become conflated with the amyloidosis model and which are actually quite separate. Here I briefly review how the prevailing view of Aβ emerged and the new findings that are changing our understanding of the role this peptide plays in AD.

Aβ has traditionally been characterized as a functionless catabolic byproduct. The idea that the peptide is metabolic “junk” has its origins in the early years of Aβ research. In the middle 1980s when Aβ was identified, this was not an unreasonable assumption. Aβ is excised from a larger precursor and the peptide’s generation requires proteolytic cleavage of the parent protein within cellular membranes. Intra-membrane cleavage was considered highly abnormal and an exclusively disease-associated proteolytic pathway. Thus, Aβ generation was thought to occur only in AD brain and, by extension, the peptide’s biological activities viewed as intrinsically abnormal. However, in the late 1990s it emerged that intra-membrane cleavage is a normal proteolytic pathway that mediates generation of a diverse range of functional biomolecules. By the early 2000s, Aβ was also known to be a normal longtime constitutive product of human and animal metabolism. Indeed, the human Aβ sequence is at least 400 million years old (humans share Aβ sequences with coelacanths, an ancient fish taxon) and is found unchanged in 60-70% of vertebrate species with only conservative modifications in the remainder. Despite the emergence of these compelling findings nearly 20 years ago, the assumption that Aβ activities, particularly the propensity for self-association, are intrinsically pathological remains widely held and underlies the majority of AD therapeutic strategies.

The remarkable age and conservation of the Aβ sequence suggest the peptide is not metabolic junk but has an important physiological function. Moreover, Aβ’s propensity to generate β-amyloid is likely to play a key role in the peptide’s normal activities. In 2010 we first proposed that Aβ belongs to a family of proteins known as antimicrobial peptides (AMPs). AMPs are natural antibiotics and the foot soldiers of innate immunity, an ancient immune system found in all animals. Innate immunity and AMPs are critically important for combating infections, particularly in the immuno-privileged brain where the actions of the adaptive immune system are highly constrained. We demonstrated that in vitro Aβ is a potent AMP with antimicrobial activity that, under some conditions, approaches penicillin1. More recently we have shown in animal models that Aβ expression protects against infection, dramatically increasing survival in some cases2. Most significantly, we have shown the protective activities of Aβ are mediated by β-amyloid generation. Pathogens become ensnared by Aβ fibrils and, finally, permanently trapped within β-amyloid deposits. Notably, this mechanism is not unique to Aβ and other ancient entrapment AMPs have been identified that sequester microbes in amyloid3. A normal physiological role for Aβ/β-amyloid in combating infection is also consistent with the finding that innate immune genes predominate as AD risk factors in recent genetic studies4. An AMP identity for Aβ, and emerging findings from genetics studies, suggest amyloidosis in AD may be part of an innate immune response to genuine, or incorrectly perceived, immuno-challenge. This stands in stark contrast to the prevailing AD model in which amyloidosis is driven solely by the unfortunate misbehavior of “badboy” Aβ. It is to be hoped that investigators will begin focusing upstream of the amyloid cascade for possible instigator’s of AD pathology, not least of which is the possibility of an infection etiology for the disease. As to the amyloid hypothesis- overwhelming evidence remains for the primacy of Aβ and β-amyloid in AD pathology. The idiom “don’t throw the baby out with the bathwater” may be applicable here. In this instance the bathwater is legacy assumptions about Aβ no longer consistent with available data. The amyloid cascade may be a key intermediate step in the AD pathological pathway rather than its genesis. In any case, there is reason to be cautiously optimistic as to the emergence of an effective AD treatment over the next decade. Early targeting of Aβ may still prove efficacious, and a drug target may emerge upstream of the amyloid cascade that is more tractable to modulation by therapeutic agents than β-amyloid generation has proven to be.

 Acknowledgements: I gratefully acknowledge the Cure Alzheimer’s Fund for their past and ongoing support.

Bibliography

1                  Soscia, S. J. et al. The Alzheimer‘s disease-associated amyloid β-protein is an antimicrobial peptide. PLoS ONE 5, e9505, doi:10.1371/journal.pone.0009505 (2010).

2                  Vijaya Kumar, D. K., Eimer, W. A., Tanzi, R. E. & Moir, R. D. Alzheimer’s disease: the potential therapeutic role of the natural antibiotic amyloid-β peptide. Neurodegener Dis Manag, doi:10.2217/nmt-2016-0035 (2016).

3                  Chu, H. et al. Human α-defensin 6 promotes mucosal innate immunity through self-assembled peptide nanonets. Science 337, 477-481, doi:10.1126/science.1218831 (2012).

4                  Tanzi, R. E. The genetics of Alzheimer disease. Cold Spring Harb Perspect Med 2, doi:10.1101/cshperspect.a006296 (2012).