The widely fluctuating blend of Alzheimer and Parkinson disease features in dementia with Lewy bodies (DLB) make it one of the most challenging neurodegenerative disorders to study. A new mouse model that debuted in this week’s Journal of Neuroscience may help. Putting a mutant α-synuclein transgene into the triple-transgenic (3xTg) Alzheimer disease model, researchers led by Frank LaFerla, University of California, Irvine, have engineered mice with pathological features of both AD and DLB. In addition to enhanced Aβ, tau, and α-synuclein lesions, the animals show faster cognitive decline. “This is so important because it potentially offers the ability to overcome the greatest unmet need in dementia with Lewy body research—a preclinical model that recapitulates both the pathology and clinical features of the disease,” said James Galvin, New York University, who served as a panelist in Alzforum’s recent DLB Webinar (see ARF related news story).

The brains of AD patients are riddled with Aβ plaques and neurofibrillary tangles, but up to half contain a third pathology—clumping of α-synuclein into Lewy bodies (Hamilton, 2000). Compared to “pure” AD cases with just plaques and tangles, triple pathology patients tend to develop more severe cognitive symptoms (Olichney et al., 1998; Kraybill et al., 2005), suggesting that Aβ, tau, and α-synuclein speed aggregation and accumulation of one another. This notion has drawn support from in vitro work suggesting that tau and α-synuclein help the other form fibrils (Giasson et al., 2003 and ARF related news story), and transgenic mouse studies showing similar synergism between α-synuclein and Aβ (Masliah et al., 2001 and ARF related news story). Thus far, scientists have addressed the synergy issue in pairs; the current study brings together all three pathologies in a single organism.

To create the DLB-AD model, joint lead authors Lani Clinton, Mathew Blurton-Jones, and Kristoffer Myczek crossed LaFerla’s 3xTg mice (which express mutated forms of amyloid precursor protein [APP], presenilin 1 [PS1], and tau) with pathogenic α-synuclein-expressing M83 mice, a transgenic line developed by Virginia Lee and coauthor John Trojanowski of the University of Pennsylvania in Philadelphia (Giasson et al., 2002 and ARF related news story). The resulting DLB-AD mice were homozygous for APP, PS1, and tau, but hemizygous for the α-synuclein transgene. (α-synuclein homozygotes develop early motor deficits and would confound behavioral analysis.)

The mice faced two cognitive tasks—the Barnes circular maze, which measures spatial memory, and an inhibitory avoidance test that assesses fear conditioning. On the former, two-month-old DLB-AD and 3xTg mice already had trouble, relative to age-matched wild-type and M83 littermates. By six months, the DLB-AD mice were doing noticeably worse than the 3xTg mice, and continued to decline until 12 months. At that point the 3xTg mice looked just as bad. The authors suggest this represents a ceiling effect. At 12 months, both 3xTg and DLB-AD mice were performing the navigation task about as poorly as possible within the assay parameters.

In the inhibitory avoidance test, deficits in the DLB-AD mice showed up later—around six months of age. Between six and nine months, the DLB-AD mice did worse than 3xTg mice, but by 12 months, the two groups performed equally poorly, and much worse than the wild-type and M83 mice. All four groups of mice had comparable motor function at all ages of analysis, easing concerns that motor deficits associated with α-synuclein overexpression interfered with the cognitive assessments. Interestingly, at 12 months of age, the M83 mice started underperforming relative to wild-type controls in the Barnes maze. “That was a pleasant, somewhat surprising finding—that α-synuclein alone could cause cognitive deficits,” LaFerla told ARF.

The neuropathology, measured by ELISA and immunohistochemistry, seemed consistent with the cognitive data. Compared to age-matched 3xTg mice, 12-month-old DLB-AD mice have higher levels of insoluble Aβ40 and Aβ42 peptides and more thioflavin-positive plaques, but no differences in APP processing or steady-state APP levels. On the tau front, year-old DLB-AD mice had decreased amounts of detergent-soluble protein and correspondingly increased levels of insoluble forms, as well as much more phospho-tau. And when the authors checked for the third pathology, they found insoluble α-synuclein accumulating in the DLB-AD mice several months earlier than it typically shows up in homozygous M83 mice. The same was true for a serine129-phosphorylated α-synuclein that appears in Lewy bodies; it was detected in the insoluble fractions of DLB-AD mice by 12 months, long before it would normally be seen in M83 single-transgenics.

Taken together, the data suggest that the effects of Aβ, tau, and α-synuclein are synergistic rather than simply additive. “If they were additive, you’d simply see the normal progression of amyloid and tau pathologies that we detect in 3xTg mice, along with the normal progression of α-synuclein pathology observed in M83 mice,” said Blurton-Jones. “Instead, we saw an acceleration of all three pathologies in the DLB-AD mice, suggesting that each pathology is modifying the rate and degree to which the other two pathologies develop."

The interplay among the pathologies is also suggested by the location of inclusions that form, Benjamin Wolozin, Boston University, noted in an e-mail to ARF. “The primary location of the α-synuclein inclusions shifts from brain stem in the mono-transgenic α-synuclein mouse to cortex and subiculum in the DLB-AD mouse, he wrote. The shift is biologically interesting because DLB does have cortical Lewy bodies, which suggests the localization change is linked to the disease process.”

Along with hastened cognitive decline, the α-synuclein localization in the DLB-AD mice “highlights the interactions between different types of inclusions,” Wolozin noted. A recent structural study describes a mechanism for interaction of Aβ and α-synuclein peptides at synaptic membranes (Mandal et al., 2006), and a paper in the May 19 Journal of Neuroscience suggests that exosomal mechanisms may help α-synuclein spread from cell to cell and thus propagate PD, and possibly DLB, pathology (Emmanouilidou et al., 2010).

Wolozin also found it striking that tau and α-synuclein inclusions in the DLB-AD quadruple-transgenic mice do not seem to colocalize within neurons, but rather form distinct aggregates. This raises the classic question of what makes neurons selectively vulnerable to certain pathologies, Wolozin noted. “It remains unclear why inclusions form in particular sets of neurons, and in the case of LaFerla’s quadruple-transgenic mice, why one set of neurons might develop tau pathology while another develops α-synuclein pathology,” he wrote. “Regardless of the ultimate answers, the model put forth by LaFerla and colleagues will go a long way toward providing tools allowing us to investigate these questions.” (See full comment below.)

On the therapeutic side, the authors plan to use the DLB-AD mice to test whether immunotherapy targeting a single pathology could mitigate others LaFerla said. His group previously found that passive immunotherapy directed at Aβ in mice can ameliorate not only plaques, but neurofibrillary tangles as well (see ARF related news story).—Esther Landhuis.

Reference:
Clinton LK, Blurton-Jones M, Myczek K, Trojanowski JQ, LaFerla FM. Synergistic Interactions between Abeta, Tau, and alpha-Synuclein: Acceleration of Neuropathology and Cognitive Decline. J. Neurosci. 26 May 2010;30(21):7281-7289. Abstract

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Comments on News and Primary Papers

  1. The pathologies occurring in Alzheimer disease (AD) are curious because of their overlap with other disorders. Although accumulation of Aβ is most commonly associated with AD, neuritic plaques are also observed in Parkinson dementia, diffuse Lewy body diseases, and other less common disorders. Similarly, tau inclusions occur in AD and frontotemporal dementia (as well as other less common diseases), and tau haplotypes are implicated in Parkinson disease. α-synuclein inclusions also occur in multiple diseases including Parkinson disease, diffuse Lewy body disease, and even AD. Prior work by Eliezer Masliah’s group produced a double-transgenic cross expressing both APP and α-synuclein, and showed enhanced accumulation of α-synuclein inclusions (Masliah et al., 2001). Similarly, John Trojanowski, Virginia Lee, and colleagues showed enhanced neurodegeneration in tau mice expressing mutant human α-synuclein (Giasson et al., 2003). The current manuscript from Frank LaFerla’s group, by Clinton et al., now pushes this idea a step further by combining his triple-transgenic model (3xTg-AD), which develops Aβ and tau inclusions, with an α-synuclein model.

    The quadruple-transgenic mice show a striking increase in accumulation of all three types of inclusions—Aβ, tau, and α-synuclein. The cognitive deficits also develop at an accelerated pace. One of the more striking aspects of the work is the location of the inclusions that form. The primary location of the α-synuclein inclusions shifts from brain stem in the mono-transgenic α-synuclein mouse to cortex and subiculum in the DLB-AD mouse. The shift in gross localization of the α-synuclein combined with the acceleration of cognitive decline highlights the interactions among these different types of inclusions. The accelerated neurodegeneration also emphasizes the additive damage associated with increasing burden of inclusions. Whether the additive damage reflects a direct mechanistic interaction of neurodegenerative pathways contributed by each type of inclusion or simply the additive burden of increased cumulative damage remains to be determined.

    Although the combined effects of the inclusions is to produce additive degenerative effects, one of the surprising observations is that the tau and α-synuclein inclusions don’t show strong colocalization within neurons. Both form distinct and separate inclusions. This observation is reminiscent of observations by Giasson and colleagues, and by my group (Frasier et al., 2005), showing the presence of phosphorylated tau in brains of α-synuclein overexpressing mice, but also showing that the phospho-tau and α-synuclein accumulated in a different set of neurons (Frasier et al., 2005; Giasson et al., 2003). These observations raise a classic theme in neurodegenerative research—that of selective neuronal vulnerability. It remains unclear why specific inclusions form in particular sets of neurons, and in the case of LaFerla’s quadruple-transgenic mice, why one set of neurons might develop tau pathology while another develops α-synuclein pathology. Regardless of the ultimate answers, the model put forth by Clinton et al. will go a long way toward providing tools allowing us to investigate these questions.

    View all comments by Benjamin Wolozin

References

Webinar Citations

  1. Betwixt and Intermixed—Dementia With Lewy Bodies

News Citations

  1. Spectrum of Neurodegeneration Comes to the Fore
  2. Tau and α-synuclein at the Nexus of Alzheimer's and Parkinson's
  3. Aβ Abets α-Synuclein
  4. Presenting: A Not-Quite-Parkinson's Mouse Model
  5. Tackling Alzheimer’s from the Outside in

Paper Citations

  1. . Lewy bodies in Alzheimer's disease: a neuropathological review of 145 cases using alpha-synuclein immunohistochemistry. Brain Pathol. 2000 Jul;10(3):378-84. PubMed.
  2. . Cognitive decline is faster in Lewy body variant than in Alzheimer's disease. Neurology. 1998 Aug;51(2):351-7. PubMed.
  3. . Cognitive differences in dementia patients with autopsy-verified AD, Lewy body pathology, or both. Neurology. 2005 Jun 28;64(12):2069-73. PubMed.
  4. . Initiation and synergistic fibrillization of tau and alpha-synuclein. Science. 2003 Apr 25;300(5619):636-40. PubMed.
  5. . beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease. Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12245-50. PubMed.
  6. . Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron. 2002 May 16;34(4):521-33. PubMed.
  7. . Interaction between Abeta peptide and alpha synuclein: molecular mechanisms in overlapping pathology of Alzheimer's and Parkinson's in dementia with Lewy body disease. Neurochem Res. 2006 Sep;31(9):1153-62. PubMed.
  8. . Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J Neurosci. 2010 May 19;30(20):6838-51. PubMed.
  9. . Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. J Neurosci. 2010 May 26;30(21):7281-9. PubMed.

Other Citations

  1. 3xTg mice

Further Reading

Papers

  1. . Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. J Neurosci. 2010 May 26;30(21):7281-9. PubMed.
  2. . beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease. Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12245-50. PubMed.
  3. . Initiation and synergistic fibrillization of tau and alpha-synuclein. Science. 2003 Apr 25;300(5619):636-40. PubMed.

Primary Papers

  1. . Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. J Neurosci. 2010 May 26;30(21):7281-9. PubMed.