Humans are not alone in accumulating Aβ in their brain. Squirrel monkeys, vervets, lemurs, apes, other nonhuman primates, and even dogs develop copious amyloid plaques and cerebral amyloid angiopathy as they age. However, most animals are spared the neurofibrillary tangles, neurodegeneration, and outright dementia that follows the onset of Aβ pathology. Does only Homo sapiens get Alzheimer’s disease? If so, why? And what can animal amyloidoses teach us about the underlying pathology of AD?
At an Alzforum webinar on Wednesday, December 7, Lary Walker, Marc Dhenain, Elizabeth Head, Patrick Hof, Cynthia Lemere, and Peter Nelson discussed whether people are uniquely susceptible to AD, what other animals can tell us about the relationship between Aβ and tau, and what research could identify key susceptibility or resistance factors.
By Lary Walker
Alzheimer’s disease is defined clinically by progressively debilitating, multidomain cognitive impairments, and pathologically by the presence of senile plaques and neurofibrillary tangles in the brain. These cardinal lesions result from the misfolding, aggregation, and auto-propagation of their principal proteinaceous components, Aβ in plaques, and tau in tangles. Current genetic, pathologic, and biomarker evidence favors the view that Aβ aggregation precedes tauopathy in the disease cascade, but that both are essential for full manifestation of Alzheimer-type dementia. Surprisingly, no condition that faithfully recapitulates all of these key characteristics of Alzheimer’s has ever been identified in a nonhuman species.
Many mammals—including dogs and nonhuman primates—naturally express an identical Aβ sequence to that in humans. As in people, Aβ misfolds and aggregates in the brains of these animals as they age. However, neurofibrillary tangles are rare to nonexistent, and profound Alzheimer’s disease-like behavioral dysfunction has never been linked to plaques and tangles in any species but humans. Understanding why the defining links connecting Aβ, tau, and cognitive decline are deficient in other mammals could disclose new pathways for therapeutic intervention.
In this webinar, panelists considered the evidence for and against the unique human vulnerability to AD; in addition, they addressed why we can’t find Alzheimer’s in other species, as well as:
- Does the shorter lifespan of nonhuman species preclude Alzheimer pathogenesis?
- Does the molecular architecture of aggregated Aβ differ? If so, are the human “strains” of Aβ more pathogenic?
- Are differences in the biology of tau important?
- What else might play a role, e.g., disparities in ApoE type, metabolic and cardiovascular status, inflammation, proteostasis, post-translational modifications, and/or the effects of biometals or the environment?
Finally, the panelists considered experimental strategies for addressing issues that might reveal uniquely human risk factors, or uniquely nonhuman protective factors, for Alzheimer’s disease.
Q: What can we learn about Alzheimer’s disease from nonhuman animals that we cannot learn from human samples?
Walker: Nonhuman species can tell us what isn’t Alzheimer’s disease. For example, we can never be sure that non-demented humans with abundant Aβ plaques in the brain at death were not on the path to Alzheimer’s disease. Aged nonhuman primates with abundant plaques, however, do not manifest neurofibrillary tangles, nor do they become demented. If we can determine what protects nonhuman species from AD pathology, we might learn why humans are vulnerable, information that could illuminate new therapeutic strategies.
It is also worth noting that many discoveries regarding the nature of plaques in the brain were made in canines and nonhuman primates, such as the ultrastructure of plaques and the neurochemical composition of the neurites surrounding plaques. In addition, the ability of antibodies to target plaques and vascular amyloid in the brain—a precursor to immunotherapeutic approaches—was first demonstrated in nonhuman primates.
Q: Was there a correlation between Aβ plaque load and CSF Aβ42 in vervets?
Lemere: These animals are mostly still alive. We have the brain tissue from a few animals that have come to autopsy, but not many. It may be a while before we can answer this question.
Q: Was CSF tau also measured in vervets and what were the plasma biomarkers that were assessed? Aβ? Tau? Others?
Lemere: Tau has not been measured in CSF or plasma in the samples we received from these animals. We have used Rules-Based Medicine proteomics and Tony Wyss-Coray’s communicome to investigate human proteins in plasma (and communicome in CSF as well). The data is still under analysis so I cannot make any statement yet about the results, other than to say that there are some markers that reflect similar changes with aging and/or AD in humans.
Q: It may be that evolutionary pressure predisposes long projection neurons in humans to form tangles as well as other cellular dysfunctions, leading to an extensive neuronal disconnection syndrome.
Hof: Indeed, I’ve been saying this for 25 years.
Walker: Yes, this is quite possible. There is certainly evidence that some neuronal types are especially vulnerable to tauopathy and degeneration in AD (see, e.g., Bussiere et al., 2003). Brain regions giving rise to long axonal connections have expanded in hominids, and it has been proposed that enhanced neuroplasticity of these areas renders cells more susceptible to tangle formation (e.g., Rapoport and Nelson, 2011).
Q: Are differences in sleep perhaps relevant, given new data on its role in glymphatic clearance?
Walker: An interesting thought. There is evidence that different primate species have different patterns of sleep (Ishikawa et al., 2016), but whether differences between humans and nonhuman species might account for the human vulnerability to AD is not known.
Hof: Yes, we should probably look more closely at the glymph. It started with Quincke, better known for the edema named after him. But he did the first glymph experiments. It may be extremely relevant, certainly also in the context of TBI/CTE.
Head: This is an interesting question! In companion dogs, a disruption of sleep-wake cycle is a major sign of cognitive dysfunction in older animals and may be a reason that owners elect to euthanize (Fast et al., 2013). There is a new paper suggesting that aged dogs with disrupted sleep show tau phosphorylation in synaptosomes and neuroinflammation (Smolek et al., 2016). Last, work from our laboratory linked disruptions in sleep-wake cycle with cognitive dysfunction in aging beagles (Siwak et al., 2003).
Q: Is the hyperphosphorylation of tau the major pathology differentiating human from other species? And if so, might PP2A activity be altered in some way that allows this in humans?
Walker: Tau becomes hyperphosphorylated in other species, but whether there are species differences in the extent or localization of hyperphosphorylation is not certain. A question raised by another participant is whether there are protective sites that are differentially phosphorylated in different species (Ittner et al., 2016); clearly more comparative work is needed to resolve these important issues, as well as the functional significance of alternative splicing and amino acid substitutions in tau.
Q: Do the panelists think that protective phosphorylation of tau, as recently published by the Ittner lab, might be relevant?
Walker: Good point: see response above.
Q: A fundamental difference is that humans engage a lot more in intellectual activities. Evidence has been shown that higher neuronal activity leads to more release of tau/Aβ into the extracellular space, which adds to the metabolic burden and potentiates the neurotoxicity. Comments?
Nelson: I think that the situation with mice is worth considering. I’m not sure about their “intellectual activities,” but I guess in this context we would presume they were at the low end of the scale for mammals. Wild-type mice don’t get plaques or tangles. But transgenic mice can get lots of plaques and, if they have human tau, lots of tangles. And, in both humans and mice, when there are tangles, there is cell death and functional impairment. This seems to argue against the intellectual activity/metabolic burden hypothesis and indicates, instead, that there are specific molecular determinants of vulnerability in the human species, which, if present in other species, causes the pathology in that context too.
Q: Currently, more and more voices are heard saying tauopathy has a crucial role in AD development, however, in hamsters during hibernation, tau tangles are not associated with impaired brain function such as cognition and long term memory. I would like to hear the speakers’ opinions.
Nelson: To the best of my knowledge, hibernating animals (e.g., hamsters) don’t get tau tangles (see e.g., Gerhauser et al., 2011). They have phosphorylated tau, which is also seen in non-tangle-bearing neurons in other species. The normal (and reversible) phosphorylation of tau is an interesting phenomenon that merits more study but shouldn’t be confused with tau tangles.
- Bussière T, Giannakopoulos P, Bouras C, Perl DP, Morrison JH, Hof PR. Progressive degeneration of nonphosphorylated neurofilament protein-enriched pyramidal neurons predicts cognitive impairment in Alzheimer's disease: stereologic analysis of prefrontal cortex area 9. J Comp Neurol. 2003 Aug 25;463(3):281-302. PubMed.
- Rapoport SI, Nelson PT. Biomarkers and evolution in Alzheimer disease. Prog Neurobiol. 2011 Dec;95(4):510-3. PubMed.
- Ishikawa A, Sakai K, Maki T, Mizuno Y, Niimi K, Oda Y, Takahashi E. Investigation of sleep-wake rhythm in non-human primates without restraint during data collection. Exp Anim. 2016 Oct 18; PubMed.
- Smolek T, Madari A, Farbakova J, Kandrac O, Jadhav S, Cente M, Brezovakova V, Novak M, Zilka N. Tau hyperphosphorylation in synaptosomes and neuroinflammation are associated with canine cognitive impairment. J Comp Neurol. 2016 Mar 1;524(4):874-95. Epub 2015 Aug 27 PubMed.
- Siwak CT, Tapp PD, Zicker SC, Murphey HL, Muggenburg BA, Head E, Cotman CW, Milgram NW. Locomotor activity rhythms in dogs vary with age and cognitive status. Behav Neurosci. 2003 Aug;117(4):813-24. PubMed.
- Ittner A, Chua SW, Bertz J, Volkerling A, van der Hoven J, Gladbach A, Przybyla M, Bi M, van Hummel A, Stevens CH, Ippati S, Suh LS, Macmillan A, Sutherland G, Kril JJ, Silva AP, Mackay J, Poljak A, Delerue F, Ke YD, Ittner LM. Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer's mice. Science. 2016 Nov 18;354(6314):904-908. PubMed.
- Gerhauser I, Wohlsein P, Ernst H, Germann PG, Baumgärtner W. Lack of detectable diffuse or neuritic plaques and neurofibrillary tangles in the brains of aged hamsters. Neurobiol Aging. 2011 Jul 8; PubMed.
- Cotman CW, Head E. The canine (dog) model of human aging and disease: dietary, environmental and immunotherapy approaches. J Alzheimers Dis. 2008 Dec;15(4):685-707. PubMed.
- Cox PA, Davis DA, Mash DC, Metcalf JS, Banack SA. Dietary exposure to an environmental toxin triggers neurofibrillary tangles and amyloid deposits in the brain. Proc Biol Sci. 2016 Jan 27;283(1823) PubMed.
- Head E, Pop V, Sarsoza F, Kayed R, Beckett TL, Studzinski CM, Tomic JL, Glabe CG, Murphy MP. Amyloid-beta peptide and oligomers in the brain and cerebrospinal fluid of aged canines. J Alzheimers Dis. 2010;20(2):637-46. PubMed.
- Heuer E, Rosen RF, Cintron A, Walker LC. Nonhuman primate models of Alzheimer-like cerebral proteopathy. Curr Pharm Des. 2012 Mar;18(8):1159-69. PubMed.
- Holzer M, Craxton M, Jakes R, Arendt T, Goedert M. Tau gene (MAPT) sequence variation among primates. Gene. 2004 Oct 27;341:313-22. PubMed.
- Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Trojanowski JQ, Vinters HV, Hyman BT, . National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach. Acta Neuropathol. 2012 Jan;123(1):1-11. PubMed.
- Morales-Corraliza J, Wong H, Mazzella MJ, Che S, Lee SH, Petkova E, Wagner JD, Hemby SE, Ginsberg SD, Mathews PM. Brain-Wide Insulin Resistance, Tau Phosphorylation Changes, and Hippocampal Neprilysin and Amyloid-β Alterations in a Monkey Model of Type 1 Diabetes. J Neurosci. 2016 Apr 13;36(15):4248-58. PubMed.
- Nelson PT, Stefansson K, Gulcher J, Saper CB. Molecular evolution of tau protein: implications for Alzheimer's disease. J Neurochem. 1996 Oct;67(4):1622-32. PubMed.
- Perez SE, Sherwood CC, Cranfield MR, Erwin JM, Mudakikwa A, Hof PR, Mufson EJ. Early Alzheimer's disease-type pathology in the frontal cortex of wild mountain gorillas (Gorilla beringei beringei). Neurobiol Aging. 2016 Mar;39:195-201. Epub 2015 Dec 31 PubMed.
- Picq JL, Aujard F, Volk A, Dhenain M. Age-related cerebral atrophy in nonhuman primates predicts cognitive impairments. Neurobiol Aging. 2012 Jun;33(6):1096-109. Epub 2010 Oct 22 PubMed.
- Rosen RF, Farberg AS, Gearing M, Dooyema J, Long PM, Anderson DC, Davis-Turak J, Coppola G, Geschwind DH, Paré JF, Duong TQ, Hopkins WD, Preuss TM, Walker LC. Tauopathy with paired helical filaments in an aged chimpanzee. J Comp Neurol. 2008 Jul 20;509(3):259-70. PubMed.
- Rosen RF, Tomidokoro Y, Farberg AS, Dooyema J, Ciliax B, Preuss TM, Neubert TA, Ghiso JA, LeVine H 3rd, Walker LC. Comparative pathobiology of β-amyloid and the unique susceptibility of humans to Alzheimer's disease. Neurobiol Aging. 2016 Aug;44:185-96. Epub 2016 May 2 PubMed.
- Roy M, Cardoso C, Dorieux O, Malgorn C, Epelbaum S, Petit F, Kraska A, Brouillet E, Delatour B, Perret M, Aujard F, Dhenain M. Age-associated evolution of plasmatic amyloid in mouse lemur primates: relationship with intracellular amyloid deposition. Neurobiol Aging. 2015 Jan;36(1):149-56. Epub 2014 Jul 18 PubMed.
- Schmidt F, Boltze J, Jäger C, Hofmann S, Willems N, Seeger J, Härtig W, Stolzing A. Detection and Quantification of β-Amyloid, Pyroglutamyl Aβ, and Tau in Aged Canines. J Neuropathol Exp Neurol. 2015 Sep;74(9):912-23. PubMed.
- Serizawa S, Chambers JK, Une Y. Beta Amyloid Deposition and Neurofibrillary Tangles Spontaneously Occur in the Brains of Captive Cheetahs (Acinonyx jubatus). Vet Pathol. 2011 Jun 28; PubMed.
- Tsukada H, Nishiyama S, Ohba H, Kanazawa M, Kakiuchi T, Harada N. Comparing amyloid-β deposition, neuroinflammation, glucose metabolism, and mitochondrial complex I activity in brain: a PET study in aged monkeys. Eur J Nucl Med Mol Imaging. 2014 Nov;41(11):2127-36. Epub 2014 Jun 12 PubMed.
- Lemere CA, Beierschmitt A, Iglesias M, Spooner ET, Bloom JK, Leverone JF, Zheng JB, Seabrook TJ, Louard D, Li D, Selkoe DJ, Palmour RM, Ervin FR. Alzheimer's disease abeta vaccine reduces central nervous system abeta levels in a non-human primate, the Caribbean vervet. Am J Pathol. 2004 Jul;165(1):283-97. PubMed.
- Frost JL, Le KX, Cynis H, Ekpo E, Kleinschmidt M, Palmour RM, Ervin FR, Snigdha S, Cotman CW, Saido TC, Vassar RJ, George-Hyslop PS, Ikezu T, Schilling S, Demuth HU, Lemere CA. Pyroglutamate-3 Amyloid-β Deposition in the Brains of Humans, Non-Human Primates, Canines, and Alzheimer Disease-Like Transgenic Mouse Models. Am J Pathol. 2013 Aug;183(2):369-81. PubMed.
- Lemere CA, Oh J, Stanish HA, Peng Y, Pepivani I, Fagan AM, Yamaguchi H, Westmoreland SV, Mansfield KG. Cerebral amyloid-beta protein accumulation with aging in cotton-top tamarins: a model of early Alzheimer's disease?. Rejuvenation Res. 2008 Apr;11(2):321-32. PubMed.
- Walker LC, Jucker M. The Exceptional Vulnerability of Humans to Alzheimer's Disease. Trends Mol Med. 2017 Jun;23(6):534-545. Epub 2017 May 5 PubMed.