. Anti-Abeta antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice. J Clin Invest. 2005 Feb;115(2):428-33. PubMed.


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  1. "Until the Last Dog(ma) Dies": Some Neuritic Dystrophy Is Reversible by Passive Immunization of PDAPP Mice
    A multidisciplinary group has demonstrated that at least some neuritic dystrophy in PDAPP mice is reversible. Holtzman from Wash U, Paul from Lilly, Mathis and Klunk from Pitt, and Bacskai and Hyman from MGH contributed their considerable talent to a new paper in the current issue of The Journal of Clinical Investigation. Using the open skull method and Congo red derivative methoxy-X04 devised by the MGH and Pittsburgh groups, respectively, the team followed with serial imaging the morphology of swollen (dystrophic) neurites surrounding cortical amyloid deposits in the PDAPP mouse. Conventional wisdom would have predicted that these swellings might be permanent, but the new paper describes how passive immunization with anti-Aβ antibodies had a significant effect on partially normalizing the shapes of the processes.

    The new paper builds on earlier work by the MGH group (Lombardo et al., 2003): The advance of the JCI paper is to study the same plaques serially during life, while the Lombardo paper relied on postmortem analysis. A key novelty is directly demonstrating a significant trend toward normalization of existing dystrophic neurites, i.e., watching the same, flagrantly abnormal neurites partially recover their normal morphology, thereby unequivocally documenting the reversibility of neuritic dystrophy.

    This dovetails well with the recent report in Neuron by Oddo and colleagues (see ARF related news story) who showed that amyloid deposits and neuritic antigens were attenuated by active immunization. Janus and colleagues (Janus et al., 2000) demonstrated Aβ-dependent behavioral deficits that were reversible with active immunization, and the Holtzman paper suggests that the same may be true for passive treatment. Together, the papers portend well for the principle that Alzheimer's pathology may be treatable, even after significant dystrophy has developed.

    This is important because the most sensitive means of detecting Alzheimer's today remains neuropsychological testing, implying, by definition, the existence of pathology and deficits that one would like to reverse, if possible. Interestingly, a recent PNAS paper (Lu et al., 2005) indicates that iconic memory deficits may predict Alzheimer's even before any important deficit is present or even otherwise detectable. All the usual mice-aren't-men caveats apply, of course, but these papers are very exciting because frontiers have been pushed back both in terms of early diagnosis as well as providing optimism for reversibility of pathology.

    View all comments by Samuel Gandy
  2. The authors used multiphoton microscopy, an elegant technique, to monitor the dynamics of neuritic plaques in living mice. They used the PDAPP;Thy-1:YFP transgenic mouse model, which develops plaque pathology and expresses yellow fluorescent protein in a subset of neurons. Through cranial windows, Aβ deposits were analyzed with injected methoxy-X04, and dystrophic neurites with YFP-induced fluorescence. Over a period of 72 hours, the amyloid-associated neurites remained stable. However, after application of the anti-Aβ antibody 10D5 to the cortical surface, the number and total cross-sectional area of dystrophic neuritis decreased significantly. This clearly demonstrates again the value of passive immunization to reduce extracellular plaque load and the associated neuritic pathology.

    Although these results are very promising, novel transgenic mouse models teach us that extracellular amyloid plaques are not a major trigger for the dramatic neuron loss and brain atrophy. On the contrary, amyloid plaques do not correlate with the hippocampal neuron loss in the transgenic models (Schmitz et al., 2004; Casas et al., 2004). In both models, the increased amount of intraneuronal Aβ42 correlates best with the loss of neurons and brain tissue. These models support the idea that neuron loss and atrophy in AD is triggered by intracellular accumulation of Aβ42, and not by extracellular amyloid pathology.

    It is very likely that intraneuronal Aβ accumulation leads not only to neuron loss, but also disrupts many neuronal functions, for example, axonal transport. Therefore, it will be very important to learn more about the influence of passive immunization on the potential to reduce intraneuronal Aβ levels as has been shown recently (Oddo et al., 2004). Using a triple-transgenic model (3xTg-AD) that develops plaques and tau lesions, the authors showed that Aβ immunotherapy reduces not only extracellular Aβ plaques, but also intracellular Aβ accumulation, and leads to the clearance of tau hyperphosphorylation.

    Convincing evidence that passive immunization is able to rescue neuronal dysfunction and neuron loss is, however, still lacking.


    . Time sequence of maturation of dystrophic neurites associated with Abeta deposits in APP/PS1 transgenic mice. Exp Neurol. 2003 Nov;184(1):247-63. PubMed.

    . Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer's disease. Am J Pathol. 2004 Apr;164(4):1495-502. PubMed.

    . Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model. Am J Pathol. 2004 Oct;165(4):1289-300. PubMed.

    . Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron. 2004 Aug 5;43(3):321-32. PubMed.

  3. Thank you for offering such a variety of papers by people who are spending their lives looking for answers.

    PS: Footnotes for lay persons would help.

    View all comments by Elizabeth Petersen
  4. This paper by the Holtzman group supports the original work of the Bacskai/Hyman group that also showed that reduction of Aβ in the brain can induce a rapid structural recovery of existing amyloid-associated neuritic dystrophy. The originality of this new paper is that the analysis was performed in a living mouse brain as opposed to postmortem in the original study published in 2003 (Lombardo et al.). The data presented support the AD-amyloid hypothesis and, indeed, suggest that reducing Aβ (via an immunotherapy, at least) will be effective.

    I would have liked to see if the same effect could be observed if the antibody is injected into the blood. Would this also reduce neurite dystrophy over the same time period? This is worthy of demonstration since, realistically, the current AD immunotherapy in development will require the injection of humanized Aβ antibodies into the bloodstream.

    Moreover, although the study clearly demonstrates histological improvements (reduction of neurite dystrophy) after the antibody treatment, it is important in the future to demonstrate if this also leads to a recovery of cognitive functions. It could also be very interesting to repeat the experiment with two kinds of antibody: one that recognizes only the monomeric form of Aβ and one that recognizes only its fibrillar form. This would answer this burning question: Shall companies develop an antibody that recognizes the fibrillar form of Aβ or its monomeric form (sink hypothesis)?

    Finally, the fact that the reduction of neuritic dystrophy can only be seen on the side ipsilateral to 10D5 application (when applied to 17-18-month-old PDAPP mice) suggests that the effect won't be observed unless there is a massive amount of antibody present.

    Altogether, this is an important paper because it shows clearly that ongoing axonal or dendritic damage by Aβ seems to be, in part, reversible.


    . Amyloid-beta antibody treatment leads to rapid normalization of plaque-induced neuritic alterations. J Neurosci. 2003 Nov 26;23(34):10879-83. PubMed.

  5. This paper by Brendza et al. elegantly confirms and extends previous studies by this group and others. It uses living PDAPP:Thy-1:YFP transgenic mice and multiphoton microscopy to show that passive immunization with anti-Aβ antibodies not only is able to reduce or eliminate cortical deposits of Aβ, but also the associated dystrophic neurites. These are novel and important studies, as they imply that the therapeutic effects of passive immunization may extend beyond fibrillar or aggregated Aβ deposits themselves to pathological dystrophic processes that are a prominent feature of Alzheimer disease (AD) brain pathology.

    This study is significant, as dystrophic processes are well-recognized but poorly understood components of AD brain pathology despite having been described nearly 20 years ago as sites of tau accumulation (e.g., Ihara, 1988). In addition, many studies have shown that dystrophic neurites also contain other elements including fragments of APP flanking the Aβ domain and neurofilament proteins (e.g., Arai et al., 1990). Although dystrophic neurites are the locus of more than 95 percent of immunohistochemically ascertainable, pathological tau amyloid as measured morphometrically (Mitchell et al., 2000), they are lesions with a complex composition and uncertain etiology. It is likely that they contribute to cognitive impairments in AD, although how they do this is incompletely understood.

    Thus, Brendza et al. point the way to render these enigmatic lesions more tractable to experimental investigation. It will be interesting to see if they or other investigators are able to take further steps toward elucidating the nature and pathological significance of dystrophic neurites with the elegant methods used in their current study. A better understanding of these issues will help clarify the extent to which dystrophic neurites should become a deliberate focus of therapeutic intervention in AD.

    Several of the investigators of the present paper also have shown recently how passive immunotherapy with anti-Aβ antibodies exacerbates cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice (Racke, 2005). It would be important to know if the methods used by Brendza et al. could be exploited to gain insight into mechanisms underlying this complication of Aβ immunotherapy.


    . Massive somatodendritic sprouting of cortical neurons in Alzheimer's disease. Brain Res. 1988 Aug 30;459(1):138-44. PubMed.

    . Defined neurofilament, tau, and beta-amyloid precursor protein epitopes distinguish Alzheimer from non-Alzheimer senile plaques. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2249-53. PubMed.

    . Novel method to quantify neuropil threads in brains from elders with or without cognitive impairment. J Histochem Cytochem. 2000 Dec;48(12):1627-38. PubMed.

    . Exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid beta. J Neurosci. 2005 Jan 19;25(3):629-36. PubMed.

  6. Brendza and colleagues demonstrate that administration of anti-Aβ antibodies into APP-transgenic mouse brain results in recovery of dystrophic neuritis surrounding Aβ plaques. The authors employed multiphoton microscopy to detect dystrophic neuritis labeled by transgene-derived YFP. This detection method allows in-vivo observation of Aβ plaques and dystrophic neuritis in living mice, although it is not fully non-invasive, as it requires cranial surgery to make a small window on a cranial bone.

    The effect of the antibody administration is not very large, but is statistically significant. The authors’ observation indicates that Aβ removal leads to recovery of neuritic dystrophy and that the processes involved in dystrophic neuritis are reversible until they reach a certain point. The results shown by Brendza and colleagues thus provide additional support for therapeutic strategies targeting Aβ.

    There remains, however, a primary question whether the formation of dystrophic neurites is a main pathway causing cognitive dysfunction in the pathological cascade of Alzheimer disease development, since it is generally accepted that tauopathy rather than Aβ amyloidosis is more closely associated with the symptoms.

    One technical point to note is that the authors administered the anti-Aβ antibodies directly into the cranial windows. This protocol probably does not mimic the processes evoked by Aβ vaccination, active or passive, because intravenously administered anti-Aβ antibodies do not seem to penetrate into brain parenchyma.

    In any case, removal of Aβ deposition in the early stages of the disease development before tauopathy and neurodegeneration proceeds to an irreversible extent will certainly stop this tragic disease from rising. Thus, the key words for combating Alzheimer disease in a pragmatic manner are “presymptomatic diagnosis” and “preventive medication.” For this purpose, we need to identify the primary cause of Aβ deposition in sporadic Alzheimer disease development.