Article

Differences in regional brain atrophy in genetic forms of Alzheimer's disease.

Prince of Wales Medical Research Institute and the University of New South Wales, Barker Street, Randwick, Sydney, NSW 2031, Australia.
Neurobiology of Aging (Impact Factor: 4.85). 04/2006; 27(3):387-93. DOI: 10.1016/j.neurobiolaging.2005.03.011
Source: PubMed

ABSTRACT Multiple degenerative hallmarks characterize Alzheimer's disease: insoluble protein deposition, neuronal loss and cortical atrophy. Atrophy begins in the medial temporal lobe and becomes global by end stage. In a small proportion of cases, these tissue changes are caused by mutations in three known genes. These cases are affected earlier in life and have more abundant protein deposition, which may indicate greater tissue atrophy and degeneration. This issue remains unresolved. Grey matter atrophy in different cortical regions was determined in genetic cases of Alzheimer's disease (N = 13) and compared to sporadic cases (N = 13) and non-diseased controls (N = 23). Genetic mutations were found to influence the degree and regional pattern of atrophy. The majority of cases had greater medial temporal atrophy than sporadic disease, suggesting that abnormalities affecting Abeta metabolism selectively increase hippocampal degeneration. Cases with mutations in presenilin-1 demonstrated additional increased frontotemporal atrophy. This effect may be due to the influence of presenilin-1 on tau phosphorylation and metabolism. These differences may explain the earlier onset ages in these different forms of Alzheimer's disease.

0 Followers
  • [Show abstract] [Hide abstract]
    ABSTRACT: γ-Secretase is a distinct proteolytic complex required for the activation of many transmembrane proteins. The cleavage of substrates by γ-secretase plays diverse biological roles in producing essential products for the organism. More than 90 transmembrane proteins have been reported to be substrates of γ-secretase. Two of the most widely known and studied of these substrates are the amyloid precursor protein (APP) and the Notch receptor, which are precursors for the generation of amyloid-β (Aβ) and the Notch intracellular domain (NICD), respectively. The wide spectrum of γ-secretase substrates has made analyses of the pathology of γ-secretase-related diseases and underlying mechanisms challenging. Inflammation is an important aspect of disease pathology that requires an in-depth analysis. γ-Secretase may contribute to disease development or progression by directly increasing and regulating production of pro-inflammatory cytokines. This review summarizes recent evidence for a role of γ-secretase in inflammatory diseases, and discusses the potential use of γ-secretase inhibitors as an effective future treatment option.
    Pharmacology [?] Therapeutics 11/2014; 147. DOI:10.1016/j.pharmthera.2014.11.005 · 7.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The discovery of monogenic forms of Alzheimer's Disease (AD) associated with mutations within PSEN1, PSEN2, and APP genes is giving a big contribution in the understanding of the underpinning mechanisms of this complex disorder. Compared with sporadic form, the phenotype associated with monogenic cases is somewhat broader including behavioural disturbances, epilepsy, myoclonus, and focal presentations. Structural and functional imaging show typical early changes also in presymptomatic monogenic carriers. Amyloid imaging and CSF tau/A β ratio may be useful in the differential diagnosis with other neurodegenerative dementias, especially, in early onset cases. However, to date any specific biomarkers of different monogenic cases have been identified. Thus, in clinical practice, the early identification is often difficult, but the copresence of different elements could help in recognition. This review will focus on the clinical and instrumental markers useful for the very early identification of AD monogenic cases, pivotal in the development, and evaluation of disease-modifying therapy.
    11/2013; 2013:689591. DOI:10.1155/2013/689591
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Presenilins (PS) are the catalytic components of gamma-secretase, an aspartyl protease that regulates through proteolytic processing the function of multiple signaling proteins. Specially relevant is the gamma-secretase-dependent cleavage of the beta-amyloid precursor protein (APP) since generates the beta-amyloid (Abeta) peptides that aggregate and accumulate in the brain of Alzheimer's disease (AD) patients. Abnormal processing and/or accumulation of Abeta disrupt synaptic and metabolic processes leading to neuron dysfunction and neurodegeneration. Studies in presenilin conditional knockout mice have revealed that presenilin-1 is essential for age-dependent Abeta accumulation and inflammation. By contrast, mutations in the presenilin genes responsible for early onset familial AD cause rapid disease progression and accentuate clinical and pathological features including inflammation. In addition, a number of loss of function mutations in presenilin-1 have been recently associated to non-Alzheimer's dementias including frontotemporal dementia and dementia with Lewy bodies. In agreement, total loss of presenilin function in the brain results in striking neurodegeneration and inflammation, which includes activation of glial cells and induction of proinflammatory genes, besides altered inflammatory responses in the periphery. Interestingly, some non-steroidal anti-inflammatory drugs that slow cognitive decline and reduce the risk of AD, decrease amyloidogenic Abeta42 levels by modulating allosterically PS/gamma-secretase. In this review, I present current evidence supporting a role of presenilin/gamma-secretase signaling on gliogenesis and gliosis in normal and pathological conditions. Understanding the cellular mechanisms regulated by presenilin/gamma-secretase during chronic inflammatory processes may provide new approaches for the development of effective therapeutic strategies for AD.
    Frontiers in Aging Neuroscience 05/2010; 2:16. DOI:10.3389/fnagi.2010.00016 · 2.84 Impact Factor