Alzheimer’s and Autoimmunity ~ Amyloid-β & Tau ~

Image from Alzheimer’s Pathology

Amyloid-β Plaques Amyloid-β protein in a healthy cell Images from A-β cleaved by β- & γ-secretasesA-β plaque forming outside the cell Neurofibrillary Tau Tangles

Overexpression of Aβ 42 peptide is indicated as a cause of amyloid plaque formation in AD. The PDAPP mouse overexpresses human Aβ 42 and develops many of the neuropathological hallmarks of AD in an age- and brain-region-dependent manner. What if Aβ 42 is presented as an immunogen; does the immune system clear β-amyloid plaques? Immunization of mice before and after the onset of disease with Aβ 42 prevented and reversed the onset of disease (i.e. morbidity, neuritic plaque formation, etc.)

Aβ 42 Immunization Prevents β-Amyloid Plaque Development 6 w/o mice PDAPP Synthetic human Aβ 42 Peptides from SAP PBS BufferUntreated Mice received 11 immunizations over 11 months. At 13 months, quantitative immunohistochemical measures determined the extent of amyloid-β burden and the prevalence of neuritic plaques, astrogliosis, and microgliosis. Experimental Setup Question: Can immunization of Aβ 42 prevent the development of AD-like pathology in young mice?

Aβ 42 Immunization Prevents β-Amyloid Plaque Development Results: Almost complete prevention of amyloid-β deposition. (1)Quantitative Imaging of Aβ burden in hippocampus: percentage of the area occupied by Aβ deposits. (2)Aβ deposition, dystrophic neurites, and plaque-associated astrocytosis prevented by Aβ 42 immunization PBSAβ 42

Aβ 42 Immunization Slows β-Amyloid Plaque Development Experimental Setup 11 m/o mice PDAPP Aβ 42 PBS Mice received several immunizations over the ensuing months. Half killed at 15 mo. (4 mo. treatment); remaining half killed at 18 mo. (7 mo. treatment). Brains were examined by image analysis and ELISA to determine the magnitude of amyloid-β burden and the extend of neuritic dystrophy, astrocytosis, and microgliosis. PDAPP Untreated Question: Can immunization of Aβ 42 slow the development of AD-like pathology in mice that already show signs of Aβ deposition?

Aβ 42 Immunization Slows β-Amyloid Plaque Development Results: 0.28% 4.87% 0.01% (3) %-cortical coverage of amyloid-β 12 m/o untreated mouse18 m/o PBS-immunized18 m/o Aβ 42 -immunized (4) Cortical Aβ deposition

(5) Cortical amyloid-β progression RetrosplenialEntorhinal Aβ 42 PBS (6) Amyloid-β deposition in molecular layer of the hippocampal dentate gyrus. Aβ 42 Immunization Slows β-Amyloid Plaque Development Results:

PDAPP-Mouse Aβ 42 -Immunization Summary Immunization with Aβ42 preceding plaque development essentially wholly prevents the development of Aβ plaques and associated neuropathology. Aβ42 injections to mice with developed plaque burden effectively slows the progression of existing pathology, substantially improving Aβ plaque burden, neuritic dystrophy, and gliosis. The mechanism resulting in plaque reduction did not seem to produce any obvious signs of damage to the neuropil of AB42-immunized mice. Histological examination of several organs, including brain and kidney, revealed no signs of immune-mediated complications, despite high levels of human APP expressed in these tissues and the significant antibody titre to endogenous mouse Aβ peptide (data not shown). Aβ42 immunization results in the generation of anti-Aβ antibodies and makes Aβ-immunoreactive monocytic/ microglial cells appear in the regions of remaining plaques. Perhaps anti-Aβ Abs facilitate clearance of amyloid-β either before deposition, or after plaque formation, by triggering monocytic/ microglial cells to clear amyloid-β using F c receptor-mediated signals.

Human Aβ 42 -Immunization Summary Neurology, July 2003 Neurology, May participants with mild to moderate AD for IM injections of Aβ42 and placebo (4:1). 6% (18/298) patients treated with Aβ42 developed meningoencephalitis (0/74 on placebo; p = 0.020). 16/18 patients had received 2 doses, one had received 1, and one had received 3 before symptoms occurred. No case occurred later than 6 months after the first immunization. Postvaccination meningoencephalitis occurred without clear relation to serum anti-Aβ42 antibody titers. T-cell and/or microglial activation may be causing the inflammation. Of the 300 Aβ42-treated patients, 59 (19.7%) developed the predetermined Ab response. However, no significant differences were found from placebo groups for all measures except the NTB—neuropsychotolerability. (0.03 +/ vs –0.20 +/- 0.45; p = 0.020). In the small subset of patients who had CSF examinations, CSF tau was decreased in antibody responders (n=11) vs. placebo subjects (n=10; p<0.001).

What about Tau Immunotherapy? Question: Since Tau tangles are associated with pathology of AD, what happens of we instigate an immune response against Tau? Answer: Tau vaccination in healthy mice induced AD-like pathology, indicated by neurofibrillary tangles, axonal damage, and gliosis. Conclusion: Mice AD-like pathologies developed from a immune response against intraneuronal tau. These data implicate an autoimmune mechanism for the development of tau-related abnormalities in AD.

Conclusion Tau is obviously not a suitable immunogen for AD immunotherapy. We must further explore the relationship between tau autoimmunity and AD pathology. If an autoimmune mechanism for tau- associated microtubule disintegration is discovered, attention can be turned to developing a treatment/cure for this autoimmune response. Aβ42 is a good target for AD immunotherapy, but much more work needs to be done. Although overwhelmingly successful in a mouse model, the success of Aβ42 injections to human AD patients had unforeseen consequences (6% of people develop CNS inflammation). Furthermore, the efficacy of these clinical trials did not demonstrate great success with various AD indicators. However, this is not reason to abandon Alzheimer’s immunotherapy research. The challenges of successfully taking a drug from mouse into man are incredible. Future treatments/cures for complex diseases (like Alzheimer’s) will have to be tailored to different subsets of the human population. A vast majority of patients injected with Aβ42 didn’t develop any negative side effects… patients should be classified and categorized into immune system subsets; i.e., identify a marker indicating a likelihood of inflammation after Aβ42-injection, then only give treatment to people who won’t develop inflammation.