Exploring the Nexus of Alzheimer’s Disease and Related Dementias with Cancer and Cancer Therapies

Recent population studies suggest an intriguing inverse relationship between several types of cancer and neurodegenerative diseases, including Alzheimer’s disease. Understanding the intersection of the underlying biology for these two distinct families of diseases with one another may offer novel approaches to identify new therapeutic approaches and possible opportunities to repurpose existing drug candidates. The Alzheimer’s Association and the Alzheimer’s Drug Discovery Foundation convened a one day workshop to delve into this discussion. Workshop participants outlined research focus areas, potential collaborations and partnerships for future action

Dietary restriction modulates alpha-synuclein expression in the aging rat cortex and hippocampus

Dietary restriction (DR) is one of the promising environmental interventions known to attenuate aging and decrease risk of age-related neurodegenerative disorders. The aim of this study was to assess the effects of DR on expression of a-synuclein, a presynaptic protein involved in pathogenesis of Parkinson's and some other neurodegenerative diseases, in the cortex and hippocampus of adult, middle-aged, late middle-aged, and aged rats. Using Real Time RT-PCR, the authors report that aging regulates the expression of alpha-synuclein in a tissue-specific manner and that long-term DR reverts the late age-related changes of alpha-synuclein expression. (c) 2007 Wiley-Liss, Inc.nul

Dietary restriction modulates alpha-synuclein expression in the aging rat cortex and hippocampus

Dietary restriction (DR) is one of the promising environmental interventions known to attenuate aging and decrease risk of age-related neurodegenerative disorders. The aim of this study was to assess the effects of DR on expression of a-synuclein, a presynaptic protein involved in pathogenesis of Parkinson's and some other neurodegenerative diseases, in the cortex and hippocampus of adult, middle-aged, late middle-aged, and aged rats. Using Real Time RT-PCR, the authors report that aging regulates the expression of alpha-synuclein in a tissue-specific manner and that long-term DR reverts the late age-related changes of alpha-synuclein expression. (c) 2007 Wiley-Liss, Inc.nul

Cholesterol, copper and Aβ in controls, MCI, AD and the AD cholesterol-lowering treatment trial (ADCLT)

Cholesterol clearly plays an influential role in promoting the production of amyloid β(Aβ) and possibly the progression of Alzheimer\u27s Disease (AD). The AD Cholesterol-Lowering Treatment trial (ADCLT; 1 year duration) tested atorvastatin and found significant benefit on measures of cognition and depressive symptoms in treated patients (N=32) compared to placebo (N=31). We assessed the circulating levels of Aβ1-40, Aβ 1-42, ceruloplasmin (copper chaperone), apolipoprotein E and HDL-cholesteroI in blood collected at each clinical visit during the ADCLT. We also determined the circulating cholesterol, ceruloplasmin, and Aβ levels in AD and MCI (mild cognitive impairment) patients, and controls (two groups stratified by function; high and low) participating in our Brain Bank Program. Each Brain Bank individual was clinically assessed for performance on the Mini-Mental Status Exam (MMSE), Rey auditory verbal learning test (AVLT), Clock draw, and UPSIT (smell identification test). Among individuals of equal age and education, scores on the MMSE were significantly reduced in AD compared to both MCI and controls, as were scores on the UPSIT. Ability on delayed verbal recall was significantly reduced in AD compared to MCI, and in MCI compared to both control groups. Performance on the Clock draw was similar for AD and MCI patients, but was significantly reduced when comparing MCI to control. Both cholesterol and ceruloplasmin levels were significantly increased in low-function controls compared to the high-function control group, but were not different from levels identified in the MCI and AD patients. Significantly increased levels of Aβ1-40 occurred in low- compared to high-function controls, with a further significant increase in MCI compared to low-function controls. Circulating Aβ1-40 levels were decreased in AD compared to MCI. Levels of Aβ1-42 were not significantly different between the groups. The slight gradual increase in circulating Aβ1-40 and Aβ1-42 levels produced by atorvastatin treatment in the ADCLT were not significant compared placebo. There was a trend for significant reduction in circulating ceruloplasmin levels after a year of atorvastatin therapy compared to levels observed at screen. The levels of HDL-cholesterol remained stable in the atorvastatin treated AD patients for 9 months and then decreased significantly compared to the placebo group at the 1-year time-point. The combined data support a role for cholesterol in AD and a possible influence of increasing circulating copper levels. The deterioration of function in controls and transition to MCI may be associated with concomitant incremental increases in circulating Aβ1-40 levels. Increased cholesterol and ceruloplasmin levels may be associated with slight deterioration in function among controls as a precursor to impairment considered MCI. The clinical benefit of atorvastatin therapy is clearly not associated with decreased circulating Aβ or increased HDL-cholesterol, but a positive influence of reduced copper (ceruloplasmin) levels may be a consideration. ©2005 Bentham Science Publishers Ltd

Isoprenoid Pathway and Sites of Action of Compounds Used in This Study

<p>FPP, farnesyl pyrophosphate; GGPP, geranylgeranyl pyrophosphate.</p

Structure and Expression of ROCK cDNAs, and Their Effect on Basal and Statin-Stimulated sAPP_α Shedding

<div><p>(A) Graphic representation of the ROCK1 constructs. Myc, Myc tag; KD, kinase domain; PH domain, pleckstrin homology domain; RBD, Rho-binding domain.</p> <p>(B) SweAPP N2a cells were transfected with GFP, CA ROCK1, or DN ROCK1 for 48 h. Cells were lysed and levels of expressed ROCK1 protein evaluated by immunoprecipitation–immunoblot as described in Methods.</p> <p>(C) Model for ROCK activity modulation by Rho.</p> <p>(D) SweAPP N2a cells were transfected for 48 h with control (GFP), CA ROCK1, or DN ROCK1 cDNAs. At the end of this incubation, cells were treated for an additional 24 h with simvastatin (Sim, 1 μM). sAPP_α and holoAPP were evaluated by immunoblot as described in Methods.</p> <p>(E) Graphic representation of data. Y-axis shows effect of treatment (in arbitrary units) divided by effect of untreated control (in arbitrary units); <i>n</i> = 3 independent experiments; *, <i>p</i> < 0.05 versus GFP; Student's <i>t</i> test). C, control.</p></div