The papers by Ma and Lindquist are important to AD research. Unlike most other neurodegenerative diseases, AD and prion diseases have in common that both are characterized by dementia and "extracellular" plaques. The present papers demonstrate that increasing the intracellular "cytosolic" pool of PrP (i.e., by inhibition of the proteasome) is especially critical for neurotoxicity. In Alzheimer's research, a growing number of articles are also suggesting that β-amyloid accumulates within neurons and that intracellular Aβ may be neurotoxic. For example, just this year Zhang et al. reported that Aβ1-42, but not Aβ42-1 or Aβ1-40, was highly neurotoxic when introduced intracellularly, and Busciglio et al. reported that in Down's syndrome Aβ-accumulating neurons showed signs of apoptosis, see related news item.

Still, the view that...  Read more

The papers by Ma and Lindquist are important to AD research. Unlike most other neurodegenerative diseases, AD and prion diseases have in common that both are characterized by dementia and "extracellular" plaques. The present papers demonstrate that increasing the intracellular "cytosolic" pool of PrP (i.e., by inhibition of the proteasome) is especially critical for neurotoxicity. In Alzheimer's research, a growing number of articles are also suggesting that β-amyloid accumulates within neurons and that intracellular Aβ may be neurotoxic. For example, just this year Zhang et al. reported that Aβ1-42, but not Aβ42-1 or Aβ1-40, was highly neurotoxic when introduced intracellularly, and Busciglio et al. reported that in Down's syndrome Aβ-accumulating neurons showed signs of apoptosis, see related news item.

Still, the view that Aβ may be neurotoxic intracellularly, as it is for PrP in prion diseases, remains very controversial. These new papers on PrP should move research on prion diseases further into studying the subcellular biology of prion accumulation and how this is influenced by the proteasome. Both fields need to learn from the evolving work by cell biologists and neuroscientists working on the ubiquitin-protaosome system, since it is becoming increasingly apparent that degradation of proteins via this system may be critical to all neurodegenerative diseases, and AD research should not be left behind.

View all comments by Gunnar K. Gouras

My colleague and I would also like to echo the importance of the connection between amyloid, tau, and neuronal dysfunction. The concept that tau levels within the neuron dictate the toxic response to Aβ clearly works in both directions. Our lab, in conjunction with the Ferreira and Binder labs, showed that primary cultures (Rapoport et al., 2002) of tau knockout neurons were resistant to Aβ-induced cell death. These same tau knockout mice were mated to APP transgenics by Mucke’s lab and they also showed that loss of tau impairs amyloid mediated damage. It stands to reason, then, that increased intraneuronal levels of hyperphosphorylated tau would promote amyloid mediated neuronal damage. Our unique bigenic mouse models (APPSw/NOS2-/- and APPSwDI/NOS2-/-) clearly demonstrate that non-mutated mouse tau becomes hyperphosphorylated at AD-like sites in the presence of amyloid deposition. Furthermore, the increased levels of amyloid and hyperphosphorylated tau are associated with profound neuronal loss in multiple brain regions (Colton et al.; Wilcock et al.). In addition to this...  Read more

My colleague and I would also like to echo the importance of the connection between amyloid, tau, and neuronal dysfunction. The concept that tau levels within the neuron dictate the toxic response to Aβ clearly works in both directions. Our lab, in conjunction with the Ferreira and Binder labs, showed that primary cultures (Rapoport et al., 2002) of tau knockout neurons were resistant to Aβ-induced cell death. These same tau knockout mice were mated to APP transgenics by Mucke’s lab and they also showed that loss of tau impairs amyloid mediated damage. It stands to reason, then, that increased intraneuronal levels of hyperphosphorylated tau would promote amyloid mediated neuronal damage. Our unique bigenic mouse models (APPSw/NOS2-/- and APPSwDI/NOS2-/-) clearly demonstrate that non-mutated mouse tau becomes hyperphosphorylated at AD-like sites in the presence of amyloid deposition. Furthermore, the increased levels of amyloid and hyperphosphorylated tau are associated with profound neuronal loss in multiple brain regions (Colton et al.; Wilcock et al.). In addition to this neuronal loss, the work by Gouras and colleagues suggest that colocalization of phospho-tau and amyloid may also affect synapses in a way that could further impair neuronal function. These intimate interconnections between tau, amyloid, synapses, and neuronal loss may be a critical starting point for the downward spiral observed in AD brains.

References:
Wilcock DM, Lewis MR, Van Nostrand WE, Davis J, Previti ML, Gharkholonarehe N, Vitek MP, Colton CA Progression of amyloid pathology to Alzheimer's disease pathology in an amyloid precursor protein transgenic mouse model by removal of nitric oxide synthase 2. Neurosci. 2008 Feb 13;28(7):1537-45. Abstract

Colton CA, Vitek MP, Wink DA, Xu Q, Cantillana V, Previti ML, Van Nostrand WE, Weinberg JB, Dawson H. NO synthase 2 (NOS2) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease Proc Natl Acad Sci U S A. 2006 Aug 22;103(34):12867-72. Abstract

Rapoport M, Dawson HN, Binder LI, Vitek MP, Ferreira A. Tau is essential to beta-amyloid-induced neurotoxicity. Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6364-9. Abstract

View all comments by Carol Colton
View all comments by Michael Vitek