Defining Molecular Targets to Prevent Alzheimer Disease

Abstract

n explosion of new techniques to explore DNA and protein biology during the last 2 decades has illuminated one of the most enigmatic and intractable subjects in biomedicine-neurodegeneration. Eponymic diseases of the nervous system that were until recently characterized by mechanistic ignorance and therapeutic nihilism are falling steadily to the power of molecular genetics, cell biology, biochemistry, and animal modeling. Alzheimer, Huntington, Creutzfeld-Jacob, and Parkinson diseases, as well as amyotrophic lateral sclerosis, spinocerebellar atrophies, frontotemporal dementia, and other previously obscure diseases, have all yielded rapid progress in the deciphering of their biochemical pathology and genetic underpinnings. This sea change in our understanding of a group of incurable diseases that confer enormous personal and societal burdens has brought us to the verge of rationally designed therapies and, in some cases, into actual human trials.

Acute inhibition of calcineurin restores associative learning and memory in Tg2576 APP transgenic mice

“…As demonstrated by ours and others' studies, Tg2576 mice at this age exhibit associative learning and memory impairments in the contextual fear conditioning test (Corcoran et al, 2002;Dineley et al, 2002;Comery et al, 2005). Several lines of evidence support the notion that early cognitive deficits in AD mouse models are triggered by oligomeric assemblies of Aβ rather than plaque-associated Aβ (Cleary et al, 2005b;Selkoe, 2005;Lesne et al, 2006). Recently, it has been demonstrated that purified oligomers (dimers and trimers as well as a 56 kDa dodecamer aggregate) of in vitro-and in vivo-produced Aβ can disrupt cognitive function (Cleary et al, 2005b;Lesne et al, 2006).…”

Acute inhibition of calcineurin restores associative learning and memory in Tg2576 APP transgenic mice

“…As demonstrated by ours and others' studies, Tg2576 mice at this age exhibit associative learning and memory impairments in the contextual fear conditioning test (Corcoran et al, 2002;Dineley et al, 2002;Comery et al, 2005). Several lines of evidence support the notion that early cognitive deficits in AD mouse models are triggered by oligomeric assemblies of Aβ rather than plaque-associated Aβ (Cleary et al, 2005b;Selkoe, 2005;Lesne et al, 2006). Recently, it has been demonstrated that purified oligomers (dimers and trimers as well as a 56 kDa dodecamer aggregate) of in vitro-and in vivo-produced Aβ can disrupt cognitive function (Cleary et al, 2005b;Lesne et al, 2006).…”

Neuronal or Glial Expression of Human Apolipoprotein E4 Affects Parenchymal and Vascular Amyloid Pathology Differentially in Different Brain Regions of Double- and Triple-Transgenic Mice

“…This is direct proof that even neuronal co-expression of ApoE4 with APP did not affect the balance of amyloidogenic to nonamyloidogenic secretase pathways. 2,3 Our data contrast with human ApoE knockin mice wherein delayed amyloid plaque deposition was claimed to be due to modulation of APP processing and elevated A␤40/42 ratio . 25 We neither find a delay, but a promotion of amyloid deposition, nor a decrease, but an increase in A␤42/40 ratio by ApoE4.…”

Neuronal Overexpression of Nogo Receptor 1 in APPswe/PSEN1(ΔE9) Mice Impairs Spatial Cognition Tasks without Influencing Plaque Formation

“…We first wanted to confirm that crossing these two mouse lines would in fact lead to increased expression of NgR1 and that the expression would be strong in the regions that are associated with plaque formation. As expected, crossing MemoFlex mice with APPswe/PSEN1 mice resulted in a strong overexpression of NgR1 in the same regions as seen in the MemoFlex mouse and these regions are also highly affected by plaque deposition both in humans and in APPswe/PSEN1 mice (Borchelt et al, 1997;Hardy and Selkoe, 2002;Selkoe, 2005). The MemoFlex/APPswe/PSEN1 mouse showed much stronger expression of NgR1 in cortex (Fig 10 A) compared to that seen in the APPswe/PSEN1 mouse (Fig 10 B).…”

Acute inhibition of calcineurin restores associative learning and memory in Tg2576 APP transgenic mice

“…As demonstrated by ours and others' studies, Tg2576 mice at this age exhibit associative learning and memory impairments in the contextual fear conditioning test (Corcoran et al, 2002;Dineley et al, 2002;Comery et al, 2005). Several lines of evidence support the notion that early cognitive deficits in AD mouse models are triggered by oligomeric assemblies of Aβ rather than plaque-associated Aβ (Cleary et al, 2005b;Selkoe, 2005;Lesne et al, 2006). Recently, it has been demonstrated that purified oligomers (dimers and trimers as well as a 56 kDa dodecamer aggregate) of in vitro-and in vivo-produced Aβ can disrupt cognitive function (Cleary et al, 2005b;Lesne et al, 2006).…”

Neuronal or Glial Expression of Human Apolipoprotein E4 Affects Parenchymal and Vascular Amyloid Pathology Differentially in Different Brain Regions of Double- and Triple-Transgenic Mice

“…This is direct proof that even neuronal co-expression of ApoE4 with APP did not affect the balance of amyloidogenic to nonamyloidogenic secretase pathways. 2,3 Our data contrast with human ApoE knockin mice wherein delayed amyloid plaque deposition was claimed to be due to modulation of APP processing and elevated A␤40/42 ratio . 25 We neither find a delay, but a promotion of amyloid deposition, nor a decrease, but an increase in A␤42/40 ratio by ApoE4.…”

Neuronal Overexpression of Nogo Receptor 1 in APPswe/PSEN1(ΔE9) Mice Impairs Spatial Cognition Tasks without Influencing Plaque Formation

“…We first wanted to confirm that crossing these two mouse lines would in fact lead to increased expression of NgR1 and that the expression would be strong in the regions that are associated with plaque formation. As expected, crossing MemoFlex mice with APPswe/PSEN1 mice resulted in a strong overexpression of NgR1 in the same regions as seen in the MemoFlex mouse and these regions are also highly affected by plaque deposition both in humans and in APPswe/PSEN1 mice (Borchelt et al, 1997;Hardy and Selkoe, 2002;Selkoe, 2005). The MemoFlex/APPswe/PSEN1 mouse showed much stronger expression of NgR1 in cortex (Fig 10 A) compared to that seen in the APPswe/PSEN1 mouse (Fig 10 B).…”

Acute inhibition of calcineurin restores associative learning and memory in Tg2576 APP transgenic mice

“…As demonstrated by ours and others' studies, Tg2576 mice at this age exhibit associative learning and memory impairments in the contextual fear conditioning test (Corcoran et al, 2002;Dineley et al, 2002;Comery et al, 2005). Several lines of evidence support the notion that early cognitive deficits in AD mouse models are triggered by oligomeric assemblies of Aβ rather than plaque-associated Aβ (Cleary et al, 2005b;Selkoe, 2005;Lesne et al, 2006). Recently, it has been demonstrated that purified oligomers (dimers and trimers as well as a 56 kDa dodecamer aggregate) of in vitro-and in vivo-produced Aβ can disrupt cognitive function (Cleary et al, 2005b;Lesne et al, 2006).…”

Neuronal or Glial Expression of Human Apolipoprotein E4 Affects Parenchymal and Vascular Amyloid Pathology Differentially in Different Brain Regions of Double- and Triple-Transgenic Mice

“…This is direct proof that even neuronal co-expression of ApoE4 with APP did not affect the balance of amyloidogenic to nonamyloidogenic secretase pathways. 2,3 Our data contrast with human ApoE knockin mice wherein delayed amyloid plaque deposition was claimed to be due to modulation of APP processing and elevated A␤40/42 ratio . 25 We neither find a delay, but a promotion of amyloid deposition, nor a decrease, but an increase in A␤42/40 ratio by ApoE4.…”

Neuronal Overexpression of Nogo Receptor 1 in APPswe/PSEN1(ΔE9) Mice Impairs Spatial Cognition Tasks without Influencing Plaque Formation

“…We first wanted to confirm that crossing these two mouse lines would in fact lead to increased expression of NgR1 and that the expression would be strong in the regions that are associated with plaque formation. As expected, crossing MemoFlex mice with APPswe/PSEN1 mice resulted in a strong overexpression of NgR1 in the same regions as seen in the MemoFlex mouse and these regions are also highly affected by plaque deposition both in humans and in APPswe/PSEN1 mice (Borchelt et al, 1997;Hardy and Selkoe, 2002;Selkoe, 2005). The MemoFlex/APPswe/PSEN1 mouse showed much stronger expression of NgR1 in cortex (Fig 10 A) compared to that seen in the APPswe/PSEN1 mouse (Fig 10 B).…”