Neurotrophin regulation of Alzheimer's disease pathology

Abstract

Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized histopathologically bythe accumulation of amyloid-β (Aβ) and hyperphosphorylation of tau protein. These two key proteinsare major contributors to neuronal toxicity and disease progression; however, the causal factorsinitiating this toxic cascade in sporadic disease are unknown. We hypothesize that the specificdegeneration of basal forebrain cholinergic neurons (BFCNs) and a decrease in neurotrophinavailability - which occur coincidentally with the disease - are key regulators of aberrant Aβaccumulation and tau hyperphosphorylation, and could constitute the molecular basis of AD pathologyin sporadic disease.Here we show that loss of BFCN innervation to the hippocampus of two pre-symptomatic mouse linesmodelling the disease (APP/PS1 and pR5 (P301L) mice) causes a reduction in hippocampal and nervegrowth factor (NGF) protein and/or brain-derived neurotrophic factor (BDNF). In APP/PS1 mice thiscorrelates with memory and learning deficits in a Morris water maze task, which is not observed inunlesioned transgenic controls and wildtype littermates – indicating an exacerbation of the disease. Lossof BFCN hippocampal innervation in APP/PS1 mice also increases the amount of totalAβ in the hippocampus, but has no additional effects on levels of tau hyperphosphorylation. Incontrast, memory deficits are not observed in pR5 tau transgenic mice following an equivalent loss ofBFCN hippocampal innervation and reduction of neurotrophin levels. Moreover, hippocampal levels oftau and hyperphosphorylated tau were comparable to that of control pR5 tau transgenic mice. The roleof neurotrophins in Aβ pathology in APP/PS1 mice was further assessed through viral knockdown ofBDNF protein in the hippocampus, and treatment with a neurotrophic c29 peptide following loss ofbasal forebrain cholinergic neurons. Although reduction of BDNF did not cause increased Aβ levels,and treatment with c29 peptide did not reduce Aβ load in the hippocampus of APP/PS1 micefollowing loss of BFCN, c29 peptide was able to rescue behavioural deficits of aged unlesionedAPP/PS1 mice.This work demonstrates that early cholinergic denervation of the hippocampus can trigger somefeatures of Alzheimer’s disease, namely reduced neurotrophin expression and increased Aβ production,but does not alone cause tau hyperphosphorylation and aggregation. These results are consistent withthe idea that tau pathology in AD may be downstream of Aβ pathology, and highlights the possibilitythat cholinergic dysfunction might be a major upstream contributing factor of sporadic Alzheimer’sdisease. Although we show that neurotrophin dysfunction is insufficient by itself to induce or prevent Aβ accumulation, enhancing neurotrophic signalling to provide cognitive benefit may be a viabletreatment strategy.