Updates in Alzheimer's disease: from basic research to diagnosis and therapies

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized pathologically by extracellular deposition of β-amyloid (Aβ) into senile plaques and intracellular accumulation of hyperphosphorylated tau (pTau) as neurofibrillary tangles. Clinically, AD patients show memory deterioration with varying cognitive dysfunctions. The exact molecular mechanisms underlying AD are still not fully understood, and there are no efficient drugs to stop or reverse the disease progression. In this review, we first provide an update on how the risk factors, including APOE variants, infections and inflammation, contribute to AD; how Aβ and tau become abnormally accumulated and how this accumulation plays a role in AD neurodegeneration. Then we summarize the commonly used experimental models, diagnostic and prediction strategies, and advances in periphery biomarkers from high-risk populations for AD. Finally, we introduce current status of development of disease-modifying drugs, including the newly officially approved Aβ vaccines, as well as novel and promising strategies to target the abnormal pTau. Together, this paper was aimed to update AD research progress from fundamental mechanisms to the clinical diagnosis and therapies.

Keywords: Alzheimer’s disease; Diagnosis; Drug development; Neurodegeneration; Tau; β-Amyloid.

Fig. 1

Amyloidogenic and non-amyloidogenic APP processing pathways. a The amyloidogenic processing pathway of APP produces full-length Aβ through BACE1 and γ-secretase cleavage. AEP cleavage at N373 and N585 makes APP more susceptible to BACE1 and thus promotes Aβ production. b The non-amyloidogenic processing pathway of APP by α-secretase within the Aβ domain or by BACE1 at Glu11 or by BACE2 at Phe20 does not produce full-length Aβ

Fig. 2

Mechanisms underlying Aβ accumulation and toxicities. a Common factors that promote Aβ production (left) or contribute to Aβ accumulation (right). b Experimentally proven processes of amyloid plaque formation. c Neural toxicities of Aβ

Fig. 3

Schematics showing basic structures of human tau. a MAPT gene, b pre-mRNA after transcription, and c the six major protein isoforms produced by alternative splicing

Fig. 4

Protein sequences and post-translational modifications of human and mouse tau proteins. a Sequence alignment of human tau (NP_005901.2) and mouse tau (NP_001033698.1). Red stars, potential phosphorylation sites only in mouse tau; black stars, potential phosphorylation sites only in human tau. The inconsistent amino acids between murine Tau430 and human Tau441 are labeled in red. b Tau phosphorylation site: red represents phosphorylation sites found exclusively in the brains of AD patients; green indicates phosphorylation sites found exclusively in non-AD human brains; blue represents the phosphorylation sites found in both non-AD and AD patients; and black represents no-phosphorylation detected. c Other identified post-translational modifications of tau proteins

Fig. 5

Mechanisms underlying tau-associated neurodegeneration in AD. a Imbalance of protein kinases and protein phosphatases leads to tau hyperphosphorylation. b Tau hyperphosphorylation inhibits acute cell apoptosis by preserving β-catenin. c Additional post-translational modifications of pTau promote its intracellular aggregation and accumulation. d Abnormally accumulated tau protein impairs multiple cellular biological functions. Tau hyperphosphorylation and accumulation forms a vicious cycle, resulting in chronic neurodegeneration as seen in AD