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Amyloid cascade hypothesis: is it true for sporadic Alzheimer’s disease

Melita Šalković-Petrišić ; Medicinski fakultet i Hrv. institut za istraživanje mozga Sveučilišta u Zagrebu, Zagreb, Hrvatska

Sažetak

Alzheimer’s disease (AD) is a neurodegenerative disorder in which reliable early clinical diagnosis is impossible. Early-onset familial AD form, caused by mutations of genes involved in Ab pathology, and prevailing late-onset sporadic AD (sAD) having age, diabetes type 2 and apolipoprotein E4 as risk factors, demonstrate convergent clinical (memory loss) and neuropathological (amyloid b /Ab/ and tau protein) changes. Leading amyloid cascade hypothesis assumes that Ab pathology is the primary cause of both AD forms, whereas other neuropathological changes are just downstream consequences. Transgenic mice AD models that are most widely used for AD pathophysiology research are designed to express human Ab-production proteins containing different mutations from their birth. Because of that transgenic mice could represent familial AD forms only, while for the sAD, the streptozotocin-intracerebroventricularly (STZ-icv) treated rats were proposed. STZ is a substance selectively toxic for peripheral insulin producing/secreting cells and insulin receptor (IR). STZ-icv application induces AD-like changes; cognitive deficits, reduction in brain glucose/ energy metabolism and cholinergic transmission, as well as gliosis and oxidative stress. Additionally, STZ-icv treatment induces time-dependent development of brain IR signaling cascade dysfunction leading to increased activity of glycogen synthase kinase-3 which results in Ab (angiopathy) and tau (hyperphosphorylation) pathology. These findings suggest that development of insulin resistant brain state precedes and triggers Ab pathology in sAD, challenging thus the amyloid cascade hypothesis when sAD is concerned. Further research is necessary to clarify this possibility of sAD ethiopathogenesis since it may reveal new AD therapeutic strategies towards to disease-modifying drugs.

Ključne riječi

Hrčak ID:

29048

URI

https://hrcak.srce.hr/29048

Datum izdavanja:

29.2.2008.

Posjeta: 2.168 *