Abstract
Hippocampal hyperactivity, ascribed to amyloid β (Aβ)-induced imbalances in neural excitation and inhibition, is found in patients with mild cognitive impairment, a prodromal stage of Alzheimer's disease (AD). To better understand the relationship between hippocampal hyperactivity and the molecular triggers of behavioral impairments in AD, we used Mn-enhanced MRI (MEMRI) to assess neuronal activity after subjecting mice to a task requiring spatial learning and memory. Depletion of endogenous tau in an amyloid precursor protein (APP) transgenic (J20) mouse line was shown to ameliorate hippocampal hyperactivity in J20 animals, tau depletion failed to reverse memory deficits associated with APP/Aβ overproduction. On the other hand, deletion of tau alleviated the hyperlocomotion displayed by APP transgenics, suggesting that the functional effects of Aβ-tau interactions reflect the temporal appearance of these molecules in individual brain areas.
Highlights
Gradual worsening of memory and eventual impairments of executive functions are the main clinical features of both sporadic and familial Alzheimer disease (AD)
In an extension of those studies, Roberson et al implicated tau protein in amyloid β (Aβ)-induced memory impairment; these authors found an amelioration of memory deficits when amyloid precursor protein transgenic (APP Tg) mice were cross-bred with tau knockout mice (Roberson et al, 2007)
High levels of APP-derived amyloid β (Aβ) have long been linked to aberrant synaptic activity (Nitsch et al, 1993; Kamenetz et al, 2003) and strong associations have been established between Aβ, hippocampal activation and memory decline in otherwise cognitively-normal older humans (Mormino et al, 2012; Elman et al, 2014; Leal et al, 2017); hippocampal hyperactivity may be a physiological accompaniment of aging in the mouse
Summary
Gradual worsening of memory and eventual impairments of executive functions are the main clinical features of both sporadic and familial Alzheimer disease (AD). The neuropathological correlates of these phenotypic characteristics include extracellular deposits of amyloid β (Aβ) that eventually form senile plaques and intracellular hyperphosphorylated tau that aggregates into neurofibrillary tangles (NFTs) Both Aβ and tau pathology are thought to contribute to the massive neuronal atrophy seen in the AD brain (Crimins et al, 2013) and genes that result in Aβ overproduction display have 100% penetrance in affected individuals (Tanzi, 2012). Tau deletion resulted in a recovery of LTP in APP Tg mice (Shipton et al, 2011) These preclinical findings are consistent with those of a recent cross-sectional study strongly suggested a causal link between NFT lesions, rather than Aβ deposits, with cognitive decline (Brier et al, 2016); the latter may explain why Aβ-targeted therapies have generally proven ineffective at halting disease progression in subjects with mild cognitive impairment (MCI), a precursor of early-to-moderate AD (Holmes et al, 2008)
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