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Mechanistic Studies of Antibody-Mediated Clearance of Tau Aggregates Using an ex vivo Brain Slice Model.

Krishnamurthy PK, Deng Y, Sigurdsson EM - Front Psychiatry (2011)

Bottom Line: Thus, clearance of neurofibrillary tangles and/or their precursors may reduce synaptic and neuronal loss associated with AD and other tauopathies.Additionally, tau and FITC-IgG were found together in an enriched lysosome fraction.In summary, antibody-mediated clearance of intracellular tau aggregates appears to occur via the lysosomal pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Neuroscience, New York University School of Medicine New York, NY, USA.

ABSTRACT
Recent studies have shown that immunotherapy clears amyloid beta (Aβ) plaques and reduces Aβ levels in mouse models of Alzheimer's disease (AD), as well as in AD patients. Tangle pathology is also relevant for the neurodegeneration in AD, and our studies have shown that active immunization with an AD related phospho-tau peptide reduces aggregated tau within the brain and slows the progression of tauopathy-induced behavioral impairments. Thus, clearance of neurofibrillary tangles and/or their precursors may reduce synaptic and neuronal loss associated with AD and other tauopathies. So far the mechanisms involved in antibody-mediated clearance of tau pathology are yet to be elucidated. In this study we have used a mouse brain slice model to examine the uptake and localization of FITC labeled anti-tau antibodies. Confocal microscopy analysis showed that the FITC labeled anti-tau antibody co-stained with phosphorylated tau, had a perinuclear appearance and co-localized with markers of the endosomal/lysosomal pathway. Additionally, tau and FITC-IgG were found together in an enriched lysosome fraction. In summary, antibody-mediated clearance of intracellular tau aggregates appears to occur via the lysosomal pathway.

No MeSH data available.


Related in: MedlinePlus

Neuronal co-localization of FITC–IgG and LAMP2. High magnification confocal microscope images of brain slice sections from a JNPL3 transgenic mouse. Brain slices were incubated with FITC–IgG from a high titer Tau 379–408[pSer396, 404] immunized mouse (green) and after sectioning co-stained with an antibody to LAMP2 (red), which is a marker of late endosomes and lysosomes. The merged image indicates areas of co-localization (green/yellow) between FITC–IgG and late endosomes/lysosomes, mainly in perinuclear areas. The neuronal morphology is clearly delineated by the regions of staining.
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Figure 2: Neuronal co-localization of FITC–IgG and LAMP2. High magnification confocal microscope images of brain slice sections from a JNPL3 transgenic mouse. Brain slices were incubated with FITC–IgG from a high titer Tau 379–408[pSer396, 404] immunized mouse (green) and after sectioning co-stained with an antibody to LAMP2 (red), which is a marker of late endosomes and lysosomes. The merged image indicates areas of co-localization (green/yellow) between FITC–IgG and late endosomes/lysosomes, mainly in perinuclear areas. The neuronal morphology is clearly delineated by the regions of staining.

Mentions: A higher magnification confocal microscope image of brain slices from a JNPL3 mouse incubated with FITC labeled phos-tau antibody and co-stained with LAMP2 clearly shows the perinuclear regions of co-staining. The delineated shape of the cell has a neuronal morphology and indicates that neurons are capable of taking up our FITC labeled phos-tau antibody (Figure 2).


Mechanistic Studies of Antibody-Mediated Clearance of Tau Aggregates Using an ex vivo Brain Slice Model.

Krishnamurthy PK, Deng Y, Sigurdsson EM - Front Psychiatry (2011)

Neuronal co-localization of FITC–IgG and LAMP2. High magnification confocal microscope images of brain slice sections from a JNPL3 transgenic mouse. Brain slices were incubated with FITC–IgG from a high titer Tau 379–408[pSer396, 404] immunized mouse (green) and after sectioning co-stained with an antibody to LAMP2 (red), which is a marker of late endosomes and lysosomes. The merged image indicates areas of co-localization (green/yellow) between FITC–IgG and late endosomes/lysosomes, mainly in perinuclear areas. The neuronal morphology is clearly delineated by the regions of staining.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198029&req=5

Figure 2: Neuronal co-localization of FITC–IgG and LAMP2. High magnification confocal microscope images of brain slice sections from a JNPL3 transgenic mouse. Brain slices were incubated with FITC–IgG from a high titer Tau 379–408[pSer396, 404] immunized mouse (green) and after sectioning co-stained with an antibody to LAMP2 (red), which is a marker of late endosomes and lysosomes. The merged image indicates areas of co-localization (green/yellow) between FITC–IgG and late endosomes/lysosomes, mainly in perinuclear areas. The neuronal morphology is clearly delineated by the regions of staining.
Mentions: A higher magnification confocal microscope image of brain slices from a JNPL3 mouse incubated with FITC labeled phos-tau antibody and co-stained with LAMP2 clearly shows the perinuclear regions of co-staining. The delineated shape of the cell has a neuronal morphology and indicates that neurons are capable of taking up our FITC labeled phos-tau antibody (Figure 2).

Bottom Line: Thus, clearance of neurofibrillary tangles and/or their precursors may reduce synaptic and neuronal loss associated with AD and other tauopathies.Additionally, tau and FITC-IgG were found together in an enriched lysosome fraction.In summary, antibody-mediated clearance of intracellular tau aggregates appears to occur via the lysosomal pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Neuroscience, New York University School of Medicine New York, NY, USA.

ABSTRACT
Recent studies have shown that immunotherapy clears amyloid beta (Aβ) plaques and reduces Aβ levels in mouse models of Alzheimer's disease (AD), as well as in AD patients. Tangle pathology is also relevant for the neurodegeneration in AD, and our studies have shown that active immunization with an AD related phospho-tau peptide reduces aggregated tau within the brain and slows the progression of tauopathy-induced behavioral impairments. Thus, clearance of neurofibrillary tangles and/or their precursors may reduce synaptic and neuronal loss associated with AD and other tauopathies. So far the mechanisms involved in antibody-mediated clearance of tau pathology are yet to be elucidated. In this study we have used a mouse brain slice model to examine the uptake and localization of FITC labeled anti-tau antibodies. Confocal microscopy analysis showed that the FITC labeled anti-tau antibody co-stained with phosphorylated tau, had a perinuclear appearance and co-localized with markers of the endosomal/lysosomal pathway. Additionally, tau and FITC-IgG were found together in an enriched lysosome fraction. In summary, antibody-mediated clearance of intracellular tau aggregates appears to occur via the lysosomal pathway.

No MeSH data available.


Related in: MedlinePlus