Foundational Genetics

Find all genes that contribute to risk for or protection against Alzheimer’s disease; prioritize those with the greatest impact.

Investigation of Certain Properties of Mitochondria Membranes Related to AD

Funding year(s): 
2008
Funding to date: 
$200,000

While the mechanism of Aβ cytotoxicity remains contentious, evidence is accumulating that membrane permiabilization plays a key role in the pathological activity of the peptide. This study will focus on role of Aβ oligomerization in the Aβ-mediated disruption of lipid bilayers.

Understanding the Cell Biology Underlying the Effects of Abeta on Synapse

Funding year(s): 
2008
Funding to date: 
$100,000

This research will attempt to understand the following central cell biological questions:

  1. What is the sub-cellular site where Aβ is secreted?
  2. Can the effects of Aβ secretion on synapses be blocked by drugs?

Preliminary data show that overproduction of either axonal or dendritic Aβ reduces spine density and plasticity at dendrites close (~ 5-10 um) to the secretion sites. The effects of Aβ on spines are sensitive to blockade of nicotinic or NMDA receptors. These studies will characterize the cell biology underlying the pathogenic effects of Aβ on synapses.

Defining the Effects of Physiological Synaptic Activity on Abeta Levels: Implications for AD

Funding year(s): 
2008
Funding to date: 
$100,000

The objective of this proposal is to determine the effect of physiological alterations in neuronal activity on ISF Aβ levels in vivo. Such information may provide important information as to how to potentially regulate the probability of whether or not Aβ will or will not ultimately aggregate in the brain and initiate the process we know of as AD. We will utilize in vivo microdialysis with concurrent electrophysiological recordings to determine how physiological changes in neuronal activity dynamically affects ISF Aβ.

miRNAs in AD Pathology

Funding year(s): 
2009
Funding to date: 
$100,000

This project will test the hypothesis that microRNAs regulate protein levels of APP and Genome Wide Association Screen (GWAS)-identified levels of APP and GWAS-identified risk genes.

Rescue of Synapses in AD Rodent Models

Funding year(s): 
2009
Funding to date: 
$100,000

Excessive synaptic loss is thought to be one of the earliest events in Alzheimer’s disease (AD). In our previous studies, we have shown that amyloid beta (Aβ), a peptide implicated in the pathogenesis of AD, is secreted in an activity-modulated manner. Furthermore, we found that secreted Aβ leads to loss of synaptic receptors (by endocytosis), synaptic depression and removal of dendritic spines, sites of excitatory synaptic transmission. We now wish to understand the following: Can synaptic loss seen in AD transgenic animals be rescued by block of synaptic receptor endocytosis?

NMDA Receptors

Funding year(s): 
2010
Funding to date: 
$100,000

The traditional signaling induced by NMDA-Rs is triggered by the Ca2+ ions that pass through the NMDA-R channel. However, preliminary data indicate that blockers at the NR2B subunit, but not the NR1 subunit or the channel of the NMDA receptor, prevent the synaptic effects of the NMDA receptor. These findings suggest that Abeta employs novel, non-ion flux NMDA-R signaling mechanisms to produce synaptic depression. These results may open up a new group of potential therapeutic targets for treatment of Alzheimer’s disease.

Mouse Model for Non-Generic Alzheimer's Disease

Researchers: 
Funding year(s): 
2010
Funding to date: 
$63,851

The SAMP8 mouse model line is a model of accelerated senescence, and interestingly, develops sparse amyloid plaques, which is remarkable given the less amyloidogeneic properties of murine Aß. Hence, the research hypothesis for this project is that by introducing the more amyloidogenic human APP at the endogenous locus, researchers will be able to more robustly mimic the onset of sporadic Alzheimer’s disease, and thereby utilize this model for pre-clinical development and for widespread distribution to other investigators in the field.

Anti-APOE Antibodies

Funding year(s): 
2010
Funding to date: 
$100,000

In this project, the researchers hypothesize that targeting apoE, a component of amyloid plaques, can result in less Aβ aggregation in the brain and decreased Aβ-related pathology and that this treatment will have fewer side effects than the use of anti-Aβ antibodies. The project will test this hypothesis in this proposal in the context of human apoE isoforms.

Brain Structure, Abeta Metabolism and Behavior in Mice Deficient in Diabetes and Alzheimer's Associated SorCS1

Researchers: 
Funding year(s): 
2010 to 2012
Funding to date: 
$100,000

This is an extension of an earlier grant. SorCS1 and SorL1/SorLA/LR11 belong to the sortilin family of vacuolar protein sorting-10 (Vps10) domain-containing proteins. Both are genetically associated with Alzheimer’s disease (AD), and SORL1 expression is decreased in the brains of patients suffering from AD. SorCS1 also is associated genetically with Types 1 and 2 diabetes mellitus (T1DM, T2DM). We have undertaken a study of the possible role(s) for SorCS1 in metabolism of the Alzheimer’s amyloid-beta peptide (Abeta) and the Abeta precursor protein (APP), to test the hypothesis that SorCS1 deficiency might be a common genetic risk factor underlying the predisposition to AD that is associated with T2DM. Overexpression of SorCS1c-myc in cultured cells caused a reduction ( p0.002) in Abeta generation. Conversely, endogenous murine Abeta40 and Abeta42 levels were increased (Abeta40, p<0.044; Abeta 42,p<0.007) in the brains of female SorCS1 hypomorphic mice, possibly paralleling the sexual dimorphism that is characteristic of the genetic associations of SorCS1 with AD and DM. Since SorL1 directly interacts with Vps35 to modulate APP metabolism, we investigated the possibility that SorCS1c-myc interacts with APP, SorL1 and/or Vps35. We readily recovered SorCS1:APP, SorCS1:SorL1 and SorCS1:Vps35 complexes from the nontransgenic mouse brain. Notably, total Vps35 protein levels were decreased by 49 percent (p<0.009) and total SorL1 protein levels were decreased by 29 percent (p<0.003) in the brains of female SorCS1 hypomorphic mice. From these data, we propose that dysfunction of SorCS1 may contribute to both the APP/Abeta disturbance underlying AD and the insulin/glucose disturbance underlying DM.

Within the past five years, late-onset Alzheimer’s disease and Type 2 Diabetes have been independently linked with the gene for a protein called SorCS1. This project’s objective is to build on this early data to first better understand the link between AD and T2D, and second to point to new potential drug targets for treating both AD and T2D.

2012: No Cost Extension

SorCS1 and SorL1/SorLA/LR11 belong to the sortilin family of vacuolar protein sorting-10 (Vps10) domain-containing proteins. Both are genetically associated with Alzheimer’s disease (AD), and SORL1 expression is decreased in the brains of patients suffering from AD. SORCS1 is also genetically associated with types 1 and 2 diabetes mellitus (T1DM, T2DM).We have undertaken a study of the possible role(s) for SorCS1 in metabolism of the Alzheimer’s amyloid-beta peptide (Abeta) and the Abeta precursor protein (APP), to test the hypothesis that Sorcs1 deficiency might be a common genetic risk factor underlying the predisposition to AD that is associated with T2DM. Overexpression of SorCS1c-myc in cultured cells caused a reduction ( p0.002) in Abeta generation. Conversely, endogenous murine Abeta40 and Abeta42 levels were increased (Abeta40 , p<0.044; Abeta 42 ,p<0.007) in the brains of female Sorcs1 hypomorphic mice, possibly paralleling the sexual dimorphism that is characteristic of the genetic associations of SORCS1 with AD and DM. Since SorL1 directly interacts with Vps35 to modulate APPmetabolism,we investigated the possibility that SorCS1c-myc interacts with APP, SorL1, and/or Vps35. We readily recovered SorCS1:APP, SorCS1:SorL1, and SorCS1:Vps35 complexes from non transgenic mouse brain. Notably, total Vps35 protein levels were decreased by 49% (p<0.009) and total SorL1 protein levels were decreased by 29% (p<0.003) in the brains of female Sorcs1 hypomorphic mice. From these data, we propose that dysfunction of SorCS1 may contribute to both the APP/Abeta disturbance underlying AD and the insulin/glucose disturbance underlying DM.