Extracellular amyloid plaques are a defining feature of Alzheimer's disease brain pathology. A poorly understood aspect of these plaques is the massive abundance of lysosomes that selectively accumulate within dystrophic (swollen) axons that pass close to them. This axonal enrichment for lysosomes stands in sharp contrast to their near exclusion from the axons of healthy neurons. Beyond the potentially negative consequences of lysosome dysregulation on neuronal proteostasis and health, the enrichment within endosomes and lysosomes of proteases ( and -secretases) responsible for amyloid (A) peptide production combined with the acidic environment of the lysosomal lumen that could further promote A nucleation and suggests a vicious cycle whereby extracellular amyloid plaques trigger axonal membrane trafficking defects that result in abnormal lysosome accumulation and enhanced production/processing of A. However, lysosomes also contain other proteases (cathepsins) that contribute to A clearance. Due to these positive and negative contributions of lysosomes to A metabolism, it is not clear whether the highly abundant lysosomes within dystrophic axons exert protective versus destructive effects on neuronal health. Thus, while there is evidence to suggest that modulating neuronal lysosome activity could represent a novel therapeutic opportunity, greater understanding of the functions of lysosomes in this context and of the basic cell biology that underlies this phenotype is required for the identification of the specific and relevant molecular targets. The proposed research builds on the unique experience in neuronal membrane traffic, lysosome homeostasis and in vivo imaging of the PI and co-PIs to address these problems in mouse models that recapitulate this Alzheimer's disease phenotype. To this end, we propose to: 1) investigate the mechanisms that give rise to the extreme abundance of lysosomes within Alzheimer's disease dystrophic axons; 2) take advantage of novel imaging-based assays for assessment of amyloid plaque formation and growth to dissect the relationship between amyloid plaque growth and neuronal lysosome function; and 3) evaluate specific strategies that modulate neuronal lysosome function in mice for their ability to protect neurons from the toxicity of abnormal - amyloid metabolism. These studies will test the hypothesis that abnormal neuronal lysosome functions are an important contributing factor to Alzheimer's disease pathology and may point to new therapeutic targets for the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
1P50AG047270-01A1
Application #
8849043
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (J1))
Project Start
Project End
Budget Start
2015-06-15
Budget End
2016-05-31
Support Year
1
Fiscal Year
2015
Total Cost
$208,125
Indirect Cost
$83,125
Name
Yale University
Department
Anatomy/Cell Biology
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06510
Wang, Tingyan; Qiu, Robin G; Yu, Ming (2018) Predictive Modeling of the Progression of Alzheimer's Disease with Recurrent Neural Networks. Sci Rep 8:9161
Crum, Jana; Wilson, Jeffrey; Sabbagh, Marwan (2018) Does taking statins affect the pathological burden in autopsy-confirmed Alzheimer's dementia? Alzheimers Res Ther 10:104
Agogo, George O; Ramsey, Christine M; Gnjidic, Danijela et al. (2018) Longitudinal associations between different dementia diagnoses and medication use jointly accounting for dropout. Int Psychogeriatr 30:1477-1487
Burke, Shanna L; Cadet, Tamara; Maddux, Marlaina (2018) Chronic Health Illnesses as Predictors of Mild Cognitive Impairment Among African American Older Adults. J Natl Med Assoc 110:314-325
Salazar, Santiago V; Cox, Timothy O; Lee, Suho et al. (2018) Alzheimer's Disease Risk Factor Pyk2 Mediates Amyloid-? Induced Synaptic Dysfunction and Loss. J Neurosci :
Kamara, Dennis M; Gangishetti, Umesh; Gearing, Marla et al. (2018) Cerebral Amyloid Angiopathy: Similarity in African-Americans and Caucasians with Alzheimer's Disease. J Alzheimers Dis 62:1815-1826
Gnjidic, Danijela; Agogo, George O; Ramsey, Christine M et al. (2018) The Impact of Dementia Diagnosis on Patterns of Potentially Inappropriate Medication Use Among Older Adults. J Gerontol A Biol Sci Med Sci 73:1410-1417
MacNeil Vroomen, Janet L; Han, Ling; Monin, Joan K et al. (2018) Diabetes, Heart Disease, and Dementia: National Estimates of Functional Disability Trajectories. J Am Geriatr Soc 66:766-772
Kent, Brianne A; Strittmatter, Stephen M; Nygaard, Haakon B (2018) Sleep and EEG Power Spectral Analysis in Three Transgenic Mouse Models of Alzheimer's Disease: APP/PS1, 3xTgAD, and Tg2576. J Alzheimers Dis 64:1325-1336
van Dyck, Christopher H (2018) Anti-Amyloid-? Monoclonal Antibodies for Alzheimer's Disease: Pitfalls and Promise. Biol Psychiatry 83:311-319

Showing the most recent 10 out of 134 publications