TY - JOUR
T1 - Is Amyloid-beta an Innocent Bystander and Marker in Alzheimer's Disease? Is the Liability of Multivalent Cation Homeostasis and its Influence on Amyloid-beta Function the Real Mechanism?
AU - ManafiRad, Arash
AU - Farzadfar, Farshad
AU - Habibi, Laleh
AU - Azhdarzadeh, Morteza
AU - Aghaverdi, Haniyeh
AU - Tehrani, Khadijeh H.
AU - Lotfi, Mina
AU - Kehoe, Patrick G.
AU - Sheidaei, Ali
AU - Ghasemian, Anoosheh
AU - Darzi, Ehsan Rezaei
AU - Mahmoodi, Ramin
AU - Mahmoudi, Morteza
PY - 2014/4/30
Y1 - 2014/4/30
N2 - Two decades of the amyloid-beta (A beta) hypothesis in Alzheimer's disease (AD) and the prominence of A beta-targeting strategies have yet to meet the levels of original expectation. Disappointing results in numerous Phase II/III studies have called for a re-examination of the validity of the A beta-targeting approaches as an intervention strategy in AD. The mid-life onset of chronic conditions (e. g., hypertension, diabetes, insulin intolerance, and depression nominated as risk factors for the later development of AD) points to the possibility that each condition could involve mechanisms, which while relatively modest over a short-term, could have significant accumulative effects. What may also not be fully appreciated is that a number of these conditions involve potential disturbances to multivalent cations (MC) levels through various mechanisms such as autophagy, oxidative stress, and apoptosis. Furthermore, some MCs have intimate associations with the mechanisms by which A beta pathology manifests. Considering various lines of evidence and incorporating statistical analysis on Disability-Adjusted Life Years (DALYs) data of both causes of and prevalence of multifactorial risk factors in different world regions, we propose an MC hypothesis for AD. More specifically, we suggest that MC imbalance marks many chronic conditions and because of their involvement with A beta pathology, could reflect that A beta may be a vital manifestation and marker of underlying MC imbalance. Thus, careful targeting of MC imbalance may provide an alternative or complementary interventional approach to current A beta treatment strategies.
AB - Two decades of the amyloid-beta (A beta) hypothesis in Alzheimer's disease (AD) and the prominence of A beta-targeting strategies have yet to meet the levels of original expectation. Disappointing results in numerous Phase II/III studies have called for a re-examination of the validity of the A beta-targeting approaches as an intervention strategy in AD. The mid-life onset of chronic conditions (e. g., hypertension, diabetes, insulin intolerance, and depression nominated as risk factors for the later development of AD) points to the possibility that each condition could involve mechanisms, which while relatively modest over a short-term, could have significant accumulative effects. What may also not be fully appreciated is that a number of these conditions involve potential disturbances to multivalent cations (MC) levels through various mechanisms such as autophagy, oxidative stress, and apoptosis. Furthermore, some MCs have intimate associations with the mechanisms by which A beta pathology manifests. Considering various lines of evidence and incorporating statistical analysis on Disability-Adjusted Life Years (DALYs) data of both causes of and prevalence of multifactorial risk factors in different world regions, we propose an MC hypothesis for AD. More specifically, we suggest that MC imbalance marks many chronic conditions and because of their involvement with A beta pathology, could reflect that A beta may be a vital manifestation and marker of underlying MC imbalance. Thus, careful targeting of MC imbalance may provide an alternative or complementary interventional approach to current A beta treatment strategies.
KW - Alzheimer's disease
KW - amyloid-beta pathology
KW - cellular integrity
KW - chronic conditions
KW - lifestyle
KW - multivalent cations homeostasis
KW - risk factors
KW - BLOOD-BRAIN-BARRIER
KW - TARGETING ANTIHYPERTENSIVE DRUGS
KW - GLYCOGEN-SYNTHASE KINASE-3
KW - PITUITARY-ADRENAL AXIS
KW - GLOBAL DNA METHYLATION
KW - OXIDATIVE STRESS
KW - ACUTE HYPERTENSION
KW - COGNITIVE DECLINE
KW - DIABETES-MELLITUS
KW - OLDER-ADULTS
U2 - 10.3233/JAD-140321
DO - 10.3233/JAD-140321
M3 - Article (Academic Journal)
C2 - 24787921
VL - 42
SP - 69
EP - 85
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
SN - 1387-2877
IS - 1
ER -