Dissociation of Amyloid Dependent Cognitive Deficits and Neurodegeneration

Identification: Lee, Michael


Dissociation of Amyloid Dependent Cognitive Deficits and Neurodegeneration
Christopher Gallardo1, Santiago Salazar4, Stephen M. Strittmatter4, Michael K. Lee2,3
1Graduate Program in Pharmacology, 2Department of Neuroscience; 3Institute for Translational Neuroscience; University of Minnesota; 4Department of Genetics, Yale University
Alzheimer's disease is clinically characterized by amyloid-β (Aβ) and tau deposition as well as neuronal loss in multiple brain regions.  A current view of AD pathogenesis is that Aβ pathology set in motion secondary insults, such as tau phosphorylation, that lead to early cognitive deficits and neurodegeneration.  Consistent with this view, numerous transgenic (Tg) mouse models demonstrate that cerebral A pathology causes memory deficits.  Unfortunately, while numerous preclinical studies using the Tg mouse model of AD have successfully attenuated cognitive dysfunction in mouse models, successful preclinical studies in AD models have failed to translate into successful therapies for humans.  One source for this could be that many of the mouse models of AD do not recapitulate progressive neurodegeneration seen in human AD and the therapeutic approached developed in mice may not attenuate progressive neurodegeneration seen in human AD.  Thus, we evaluated whether attenuation of cognitive deficits in the APPswe/PS1E9 mouse models lacking putative mediators of A toxicity (tau or cellular prion protein/prpc) was accompanied by attenuation of A-dependent. While, APPswe/PS1E9 model do not exhibit forebrain neurodegeneration, this model recapitulates progressive monoaminergic (MAergic) neurodegeneration seen in human AD cases.  Previous study showed that prpc is required for cognitive deficit in APPswe/PS1E9 model and our results show that the loss of tau prevents memory deficits in APPswe/PS1E9 model.  However, analysis of the noradrenergic (NA) axons and cell bodies show that neurodegeneration of NA neurotransmitter system was not attenuated by loss of prpc or tau expression.  The lack of neuroprotection with the loss of tau was particularly surprising as the cell culture studies have shown that the tau expression is essential for A neurotoxicity.  Collectively, our results indicate that A pathology lead to multiple pathogenic pathways represented by reversible memory dysfunction and irreversible MAergic neurodegeneration.   
Funding: I01 BX001639, R01AG029401, Susan and David Plimpton Fund (MKL)


Credits: None available.

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